Selective antigen‐specific CD4+ T‐cell,but not CD8+ T‐ or B‐cell,tolerance corrupts cancer immunotherapy |
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| Authors: | Adam E. Snook Michael S. Magee Stephanie Schulz Scott A. Waldman |
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| Affiliation: | Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA |
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| Abstract: | Self‐tolerance, presumably through lineage‐unbiased elimination of self‐antigen‐specific lymphocytes (CD4+ T, CD8+ T, and B cells), creates a formidable barrier to cancer immunotherapy. In contrast to this prevailing paradigm, we demonstrate that for some antigens, self‐tolerance reflects selective elimination of antigen‐specific CD4+ T cells, but preservation of CD8+ T‐ and B‐cell populations. In mice, antigen‐specific CD4+ T‐cell tolerance restricted CD8+ T‐ and B‐cell responses targeting the endogenous self‐antigen guanylyl cyclase c (GUCY2C) in colorectal cancer. Although selective CD4+ T‐cell tolerance blocked GUCY2C‐specific antitumor immunity and memory responses, it offered a unique solution to the inefficacy of GUCY2C vaccines through recruitment of self‐antigen‐independent CD4+ T‐cell help. Incorporating CD4+ T‐cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4+ T‐cell help, revealing the latent functional capacity of GUCY2C‐specific CD8+ T‐ and B‐cell pools, producing durable antitumor immunity without autoimmunity. Incorporating CD4+ T‐cell epitopes from foreign antigens into vaccines targeting self‐antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4+ T‐cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self‐antigens characterized by selective CD4+ T‐cell tolerance and abrogation of such tolerance through self‐antigen‐independent T‐cell help is essential for future immunotherapeutics. |
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| Keywords: | Immunotherapy T helper (Th) cells Tolerance Tumor immunology Vaccination |
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