Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy

Dodagatta-Marri, E.; Ma, H.-Y.; Liang, B.; Li, J.; Meyer, D. S.; Sun, K.-H.; Ren, X.; Zirak, B.; Rosenblum, M. D.; Headley, M.; Pinzas, L.; Reed, N. I.; Del Cid, J. S.; Adoumie, M.; Hann, B. C.; Yang, S.; Giddabasappa, A.; Noorbehesht, K.; Yang, B.; Dal Porto, J.; Tsukui, T.; Niessen, K.; Atakilit, A.; Akhurst, R. J.; Sheppard, D.

doi:10.1101/2020.05.14.084913

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bioRxiv · 10.1101/2020.05.14.084913

Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy

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Abstract

The v{beta}8 integrin is a key activator of transforming growth factor {beta} (TGF {beta}), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that v{beta}8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against v{beta}8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. v{beta}8 is expressed on tumor cells in some of these models, but tumor cell expression of v{beta}8 is not essential for the beneficial effects of ADWA-11 therapy. v{beta}8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGF{beta} and are involved in tumor cell killing, including Granzyme B and Interferon-{gamma}. These findings solidify v{beta}8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.

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Dodagatta-Marri, E., Ma, H.-Y., Liang, B., Li, J., Meyer, D. S., Sun, K.-H., Ren, X., Zirak, B., Rosenblum, M. D., Headley, M., Pinzas, L., Reed, N. I., Del Cid, J. S., Adoumie, M., Hann, B. C., Yang, S., Giddabasappa, A., Noorbehesht, K., Yang, B., Dal Porto, J., Tsukui, T., Niessen, K., Atakilit, A., Akhurst, R. J., Sheppard, D.. 2020-05-15. Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy. https://doi.org/10.1101/2020.05.14.084913

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