Key Player in Cancer Immunity Uncovered / Scoperto elemento chiave nell'immunità al cancro.
Key Player in Cancer Immunity Uncovered / Scoperto elemento chiave nell'immunità al cancro.
Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa
The immune system must strike an exquisite balance between vanquishing infections and cancer, while at the same time restraining its activity to avoid inadvertently attacking the body’s healthy tissues and organs.
This balancing feat is accomplished by a host of regulatory genes that calibrate the immune response. When this calibration goes awry, the immune system may fail to ward off cancer or it might cause autoimmunity.
Now, a group of investigators led by researchers in the Blavatnik Institute at Harvard Medical have shown that disrupting a key immune regulator, a gene called PTPN2, boosts anti-tumor immunity and enables cancer clearance in animal models.
The team’s findings are published in Nature Immunology.
Specifically, the work demonstrates that deleting the gene from the immune system of mice harboring cancer stimulates the production and fitness of cancer-and-infection-fighting immune cells known as T-killer cells.
In one experiment, deleting the PTPN2 gene from the immune systems of mice eradicated colon cancer in all animals. In another, the approach combined with PD-1 checkpoint blockade successfully eliminated a particularly aggressive and treatment-resistant form of melanoma in one-fourth of the mice with this form of cancer.
The researchers say that their findings can inform the design of therapies that target this particular immune regulator as a way to boost the body’s anti-tumor response, but further testing of the approach will be needed in animal models and in human clinical trials.
“PTPN2 represents an especially tantalizing target for cancer immunotherapy given its role in reining in anti-tumor immune signaling,” said study senior author Arlene Sharpe, chair of the Department of Immunology at Harvard Medical School.
“We are encouraged by what we found. There are critical similarities between the immune systems of mice and humans, which gives us hope that this strategy may eventually translate into humans, but there is much more work to be done,” she said.
Indeed, the researchers added, these latest findings echo the early results from animal studies conducted back in the mid-2000s that eventually led to the development of a class of immunotherapies known as checkpoint blockade inhibitors. These therapies are now regularly used in the clinic to treat a variety of cancers, including melanoma, non-small cell lung cancer and colorectal cancer.
Sharpe and study co-author Gordon Freeman, Harvard Medical School professor of medicine at Dana-Farber Cancer Institute, along with others, conducted some of the pivotal work that laid the groundwork for checkpoint blockade therapies.
“We are hopeful that our new findings could be harnessed for the development of both cell-based cancer therapies and PTPN2 small molecule inhibitors that augment current checkpoint blockade treatments,” said study first author Martin LaFleur, research fellow in Immunology in Sharpe’s laboratory.
The investigators focused on the PTPN2 gene because previous research had shown that eliminating this gene from the immune systems of mice triggered a robust immune response in animals with viral infections.
The earlier study demonstrated that deleting the PTPN2 gene powerfully boosted the production of T-killer cells, a class of immune cells that are part of the body’s adaptive immune system and critical in warding off viral and bacterial invaders and for tumor surveillance.
The earlier research established the role of PTPN2 in virally induced T-cell dysfunction. More importantly, the study pointed to PTPN2 deletion as a possible way to help immune cells overcome cancer-induced dysfunction, a phenomenon known as T-cell exhaustion.
In the current study, an initial round of experiments demonstrated that PTPN2 dampens immunity by reducing the frequency with which progenitor T cells matured into killer T-cells, also known as cytotoxic T cells. In these experiments, deleting PTPN2 induced more robust production of T-killer cells in the presence of viral infection.
Further analyses showed that PTPN2 dampens the immune response in the presence of viruses by interfering with T- killer cells’ ability to sense the distress signals sent by an immune signaling chemical called interferon alpha, which is typically triggered by viruses and cancerous cells.
This distress signal does three things: First, it warns neighboring cells of approaching contagion. Second, it activates antigen-presenting cells, so called because their function is to grab pieces of an invading or cancerous cell and present it to T-killer cells for destruction. Third, it helps promote the differentiation of progenitor T cells into T-killer cells.
The experiments further revealed that PTPN2 dampens T-cell responses to interferons by altering the downstream signaling molecules activated as a result of the distress signal.
As part of its immune function, interferon alpha also encourages the conversion of progenitor T cells into T-killer cells, so the researchers wondered whether deleting PTPN2 from immune cells could also boost response to interferon as a way to stimulate the maturation of T-killer cells.
Indeed, experiments showed that deleting PTPN2 stimulated more progenitor T cells to become T-killer cells. But the elimination of PTPN2 did more than that. It boosted not only the rate of maturation of T-cells but also their fitness and cancer-killing abilities. Specifically, these cells produced greater amounts granzyme B, a protein released by T-killer into target cells that forces them to self-destruct.
“The T cells of mice lacking PTPN2 were simply better at killing tumors,” LaFleur said.
Deleting PTPN2 in a group of mice harboring colon cancer rendered all the animals tumor-free. The approach in combination with PD-1 checkpoint blockade therapy also showed promise in a group of animals that had a form of aggressive, treatment-resistant melanoma.
Indeed, PTPN2 deletion in combination with PD-1 checkpoint blockade treatment induced tumor clearance in one-fourth of animals with this form of melanoma and slowed down tumor growth. In comparison, mice receiving PD-1 checkpoint therapy alone did not experience tumor clearance.
Taken together, these findings identify a promising new target for cancer therapy, the team said.
The design of PTPN2-based therapies could be approached in two ways. One approach would involve isolating immune cells from patients and optimizing their anti-tumor capabilities by deleting PTPN2, then reintroducing them in the body.
A second approach could be developing compounds that selectively block the activity of PTPN2. The latter strategy, the scientists said, could be used alone or in combination with checkpoint blockade therapies.
"Identifying and prioritizing therapeutic targets that simultaneously improve the immune system’s response to the tumor and also make the tumor more susceptible to immune attack should lead to even more potent treatments,” LaFleur said.
This balancing feat is accomplished by a host of regulatory genes that calibrate the immune response. When this calibration goes awry, the immune system may fail to ward off cancer or it might cause autoimmunity.
Now, a group of investigators led by researchers in the Blavatnik Institute at Harvard Medical have shown that disrupting a key immune regulator, a gene called PTPN2, boosts anti-tumor immunity and enables cancer clearance in animal models.
The team’s findings are published in Nature Immunology.
Specifically, the work demonstrates that deleting the gene from the immune system of mice harboring cancer stimulates the production and fitness of cancer-and-infection-fighting immune cells known as T-killer cells.
In one experiment, deleting the PTPN2 gene from the immune systems of mice eradicated colon cancer in all animals. In another, the approach combined with PD-1 checkpoint blockade successfully eliminated a particularly aggressive and treatment-resistant form of melanoma in one-fourth of the mice with this form of cancer.
The researchers say that their findings can inform the design of therapies that target this particular immune regulator as a way to boost the body’s anti-tumor response, but further testing of the approach will be needed in animal models and in human clinical trials.
“PTPN2 represents an especially tantalizing target for cancer immunotherapy given its role in reining in anti-tumor immune signaling,” said study senior author Arlene Sharpe, chair of the Department of Immunology at Harvard Medical School.
“We are encouraged by what we found. There are critical similarities between the immune systems of mice and humans, which gives us hope that this strategy may eventually translate into humans, but there is much more work to be done,” she said.
Indeed, the researchers added, these latest findings echo the early results from animal studies conducted back in the mid-2000s that eventually led to the development of a class of immunotherapies known as checkpoint blockade inhibitors. These therapies are now regularly used in the clinic to treat a variety of cancers, including melanoma, non-small cell lung cancer and colorectal cancer.
Sharpe and study co-author Gordon Freeman, Harvard Medical School professor of medicine at Dana-Farber Cancer Institute, along with others, conducted some of the pivotal work that laid the groundwork for checkpoint blockade therapies.
“We are hopeful that our new findings could be harnessed for the development of both cell-based cancer therapies and PTPN2 small molecule inhibitors that augment current checkpoint blockade treatments,” said study first author Martin LaFleur, research fellow in Immunology in Sharpe’s laboratory.
The investigators focused on the PTPN2 gene because previous research had shown that eliminating this gene from the immune systems of mice triggered a robust immune response in animals with viral infections.
The earlier study demonstrated that deleting the PTPN2 gene powerfully boosted the production of T-killer cells, a class of immune cells that are part of the body’s adaptive immune system and critical in warding off viral and bacterial invaders and for tumor surveillance.
The earlier research established the role of PTPN2 in virally induced T-cell dysfunction. More importantly, the study pointed to PTPN2 deletion as a possible way to help immune cells overcome cancer-induced dysfunction, a phenomenon known as T-cell exhaustion.
In the current study, an initial round of experiments demonstrated that PTPN2 dampens immunity by reducing the frequency with which progenitor T cells matured into killer T-cells, also known as cytotoxic T cells. In these experiments, deleting PTPN2 induced more robust production of T-killer cells in the presence of viral infection.
Further analyses showed that PTPN2 dampens the immune response in the presence of viruses by interfering with T- killer cells’ ability to sense the distress signals sent by an immune signaling chemical called interferon alpha, which is typically triggered by viruses and cancerous cells.
This distress signal does three things: First, it warns neighboring cells of approaching contagion. Second, it activates antigen-presenting cells, so called because their function is to grab pieces of an invading or cancerous cell and present it to T-killer cells for destruction. Third, it helps promote the differentiation of progenitor T cells into T-killer cells.
The experiments further revealed that PTPN2 dampens T-cell responses to interferons by altering the downstream signaling molecules activated as a result of the distress signal.
As part of its immune function, interferon alpha also encourages the conversion of progenitor T cells into T-killer cells, so the researchers wondered whether deleting PTPN2 from immune cells could also boost response to interferon as a way to stimulate the maturation of T-killer cells.
Indeed, experiments showed that deleting PTPN2 stimulated more progenitor T cells to become T-killer cells. But the elimination of PTPN2 did more than that. It boosted not only the rate of maturation of T-cells but also their fitness and cancer-killing abilities. Specifically, these cells produced greater amounts granzyme B, a protein released by T-killer into target cells that forces them to self-destruct.
“The T cells of mice lacking PTPN2 were simply better at killing tumors,” LaFleur said.
Deleting PTPN2 in a group of mice harboring colon cancer rendered all the animals tumor-free. The approach in combination with PD-1 checkpoint blockade therapy also showed promise in a group of animals that had a form of aggressive, treatment-resistant melanoma.
Indeed, PTPN2 deletion in combination with PD-1 checkpoint blockade treatment induced tumor clearance in one-fourth of animals with this form of melanoma and slowed down tumor growth. In comparison, mice receiving PD-1 checkpoint therapy alone did not experience tumor clearance.
Taken together, these findings identify a promising new target for cancer therapy, the team said.
The design of PTPN2-based therapies could be approached in two ways. One approach would involve isolating immune cells from patients and optimizing their anti-tumor capabilities by deleting PTPN2, then reintroducing them in the body.
A second approach could be developing compounds that selectively block the activity of PTPN2. The latter strategy, the scientists said, could be used alone or in combination with checkpoint blockade therapies.
"Identifying and prioritizing therapeutic targets that simultaneously improve the immune system’s response to the tumor and also make the tumor more susceptible to immune attack should lead to even more potent treatments,” LaFleur said.
ITALIANO
Il sistema immunitario deve trovare uno squisito equilibrio tra la lotta alle infezioni e il cancro, mentre allo stesso tempo limita la sua attività per evitare di attaccare inavvertitamente i tessuti e gli organi sani del corpo.
Questa impresa equilibrante è realizzata da una serie di geni regolatori che calibrano la risposta immunitaria. Quando questa calibrazione non funziona, il sistema immunitario potrebbe non riuscire a scongiurare il cancro o potrebbe causare autoimmunità.
Ora, un gruppo di ricercatori guidati da ricercatori dell'Istituto Blavatnik di Harvard Medical ha dimostrato che l'interruzione di un regolatore immunitario chiave, un gene chiamato PTPN2, aumenta l'immunità antitumorale e consente l'eliminazione del cancro nei modelli animali.
I risultati del team sono pubblicati su Nature Immunology.
In particolare, il lavoro dimostra che l'eliminazione del gene dal sistema immunitario dei topi che ospitano il cancro stimola la produzione e l'idoneità delle cellule immunitarie che combattono il cancro e le infezioni note come cellule T-killer.
In un esperimento, l'eliminazione del gene PTPN2 dal sistema immunitario dei topi ha sradicato il cancro del colon in tutti gli animali. In un altro, l'approccio combinato con il blocco del checkpoint PD-1 ha eliminato con successo una forma particolarmente aggressiva e resistente al trattamento del melanoma in un quarto dei topi con questa forma di cancro.
I ricercatori affermano che i loro risultati possono informare la progettazione di terapie che colpiscono questo particolare regolatore immunitario come un modo per aumentare la risposta antitumorale del corpo, ma saranno necessari ulteriori test dell'approccio nei modelli animali e negli studi clinici sull'uomo.
"La PTPN2 rappresenta un obiettivo particolarmente allettante per l'immunoterapia antitumorale, dato il suo ruolo nel reining nella segnalazione immunitaria antitumorale", ha affermato la scrittrice senior dello studio Arlene Sharpe, presidente del Dipartimento di Immunologia della Harvard Medical School.
"Siamo incoraggiati da ciò che abbiamo trovato. Ci sono somiglianze critiche tra i sistemi immunitari di topi e umani, il che ci fa sperare che questa strategia possa eventualmente tradursi in umani, ma c'è ancora molto lavoro da fare ", ha detto.
In effetti, hanno aggiunto i ricercatori, questi ultimi risultati fanno eco ai primi risultati degli studi sugli animali condotti a metà degli anni 2000 che alla fine hanno portato allo sviluppo di una classe di immunoterapie note come inibitori del blocco del checkpoint. Queste terapie sono ora regolarmente utilizzate in clinica per trattare una varietà di tumori, tra cui melanoma, carcinoma polmonare non a piccole cellule e carcinoma del colon-retto.
Sharpe e co-autore Gordon Freeman, professore di medicina della Harvard Medical School presso il Dana-Farber Cancer Institute, insieme ad altri, hanno condotto alcuni dei lavori cardine che hanno gettato le basi per le terapie per il blocco dei checkpoint.
"Speriamo che le nostre nuove scoperte possano essere sfruttate per lo sviluppo di terapie antitumorali basate su cellule e di inibitori delle piccole molecole PTPN2 che aumentano gli attuali trattamenti di blocco del checkpoint", ha affermato il primo autore dello studio Martin LaFleur, ricercatore in Immunology nel laboratorio di Sharpe.
I ricercatori si sono concentrati sul gene PTPN2 perché ricerche precedenti avevano dimostrato che l'eliminazione di questo gene dal sistema immunitario dei topi ha innescato una risposta immunitaria robusta negli animali con infezioni virali.
Lo studio precedente ha dimostrato che l'eliminazione del gene PTPN2 ha potenziato potentemente la produzione di cellule T-killer, una classe di cellule immunitarie che fanno parte del sistema immunitario adattivo del corpo e fondamentali per allontanare gli invasori virali e batterici e per la sorveglianza del tumore.
La ricerca precedente ha stabilito il ruolo di PTPN2 nella disfunzione delle cellule T indotta viralmente. Ancora più importante, lo studio ha indicato la delezione di PTPN2 come un possibile modo per aiutare le cellule immunitarie a superare la disfunzione indotta dal cancro, un fenomeno noto come esaurimento delle cellule T.
In questo studio, una serie iniziale di esperimenti ha dimostrato che PTPN2 smorza l'immunità riducendo la frequenza con cui le cellule T progenitrici maturano in cellule T killer, note anche come cellule T citotossiche. In questi esperimenti, l'eliminazione di PTPN2 ha indotto una produzione più robusta di cellule T-killer in presenza di infezione virale.
Ulteriori analisi hanno mostrato che PTPN2 smorza la risposta immunitaria in presenza di virus interferendo con la capacità delle cellule T-killer di rilevare i segnali di pericolo inviati da una sostanza chimica di segnalazione immunitaria chiamata interferone alfa, che è tipicamente innescata da virus e cellule cancerose.
Questo segnale di soccorso fa tre cose: in primo luogo, avverte le cellule vicine di contagio in avvicinamento. In secondo luogo, attiva le cellule presentanti l'antigene, così chiamate perché la loro funzione è quella di afferrare pezzi di una cellula invasiva o cancerosa e presentarla alle cellule T-killer per la distruzione. Terzo, aiuta a promuovere la differenziazione delle cellule T progenitrici in cellule T-killer.
Gli esperimenti hanno inoltre rivelato che PTPN2 smorza le risposte delle cellule T agli interferoni alterando le molecole di segnalazione a valle attivate a seguito del segnale di soccorso.
Come parte della sua funzione immunitaria, l'interferone alfa incoraggia anche la conversione delle cellule T progenitrici in cellule T-killer, quindi i ricercatori si sono chiesti se l'eliminazione di PTPN2 dalle cellule immunitarie potrebbe anche aumentare la risposta all'interferone come un modo per stimolare la maturazione di T-killer le cellule.
In effetti, gli esperimenti hanno dimostrato che l'eliminazione di PTPN2 ha stimolato più cellule T progenitrici a diventare cellule T-killer. Ma l'eliminazione di PTPN2 ha fatto di più. Ha aumentato non solo il tasso di maturazione delle cellule T, ma anche le loro capacità di fitness e di uccidere il cancro. Nello specifico, queste cellule producevano quantità maggiori di granzima B, una proteina rilasciata dal T-killer nelle cellule bersaglio che le costringe ad autodistruggersi.
"Le cellule T di topi privi di PTPN2 erano semplicemente migliori nell'uccidere i tumori", ha detto LaFleur.
L'eliminazione di PTPN2 in un gruppo di topi che ospitano il cancro del colon ha reso tutti gli animali liberi da tumore. L'approccio in combinazione con la terapia con blocco del checkpoint PD-1 ha anche mostrato risultati promettenti in un gruppo di animali che presentavano una forma di melanoma aggressivo e resistente al trattamento.
In effetti, la delezione di PTPN2 in combinazione con il trattamento con blocco del checkpoint PD-1 ha indotto la clearance tumorale in un quarto degli animali con questa forma di melanoma e ha rallentato la crescita tumorale. In confronto, i topi sottoposti alla terapia del checkpoint PD-1 da solo non hanno avuto la clearance del tumore.
Nel loro insieme, questi risultati identificano un nuovo promettente target per la terapia del cancro, ha detto il team.
La progettazione di terapie basate su PTPN2 potrebbe essere affrontata in due modi. Un approccio potrebbe consistere nell'isolare le cellule immunitarie dai pazienti e nell'ottimizzare le loro capacità antitumorali eliminando PTPN2, quindi reintroducendole nel corpo.
Un secondo approccio potrebbe essere lo sviluppo di composti che bloccano selettivamente l'attività di PTPN2. Quest'ultima strategia, hanno affermato gli scienziati, potrebbe essere utilizzata da sola o in combinazione con terapie di blocco del checkpoint.
"L'identificazione e la definizione delle priorità degli obiettivi terapeutici che contemporaneamente migliorano la risposta del sistema immunitario al tumore e rendono il tumore più suscettibile all'attacco immunitario dovrebbero portare a trattamenti ancora più potenti", ha affermato LaFleur.
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