Tumor Burden Affects Efficacy of Combination Immunotherapy

Co-targeting immune checkpoint pathways has emerged as a promising therapeutic strategy against certain cancer types, yet such strategies often fail or even contribute to tumor progression. Understanding the mechanism underlying these differential responses can help inform development of future therapeutic approaches. Pai and colleagues show that combined inhibition of CTLA4 and PD-L1 is effective against established tumors with high tumor burden (HTB), yet the same treatment strategy compromises antitumor efficacy in preclinical models with low tumor burden (LTB). In mice bearing TRAMP-C2 tumors, combined immune checkpoint blockade with anti-CTLA4 and anti–PD-L1 therapies improved antitumor activity in mice with HTB via an intratumoral decrease in regulatory T (Treg) cells and increase in CD8⁺ T cells. However, combination treatment in an LTB setting resulted in significantly larger tumor growth than treatment with anti-CTLA4 alone. The same reduced response to combination treatment was observed in patients with melanoma with low disease burden, indicating that PD-1 blockade compromises the antitumor efficacy of anti-CTLA4 monotherapy in an LTB setting. Mechanistically, combination treatment in mice with LTB resulted in loss of CD8⁺ T cells specific to the dominant SPAS1 antigen via induction of apoptosis and cell death pathways in these cells. These T cells expressed higher levels of IFNγ receptor, which made them more susceptible to IFNγ-induced activation of caspase-3 than their naïve counterparts. Conversely, combination treatment in Ifng knockout mice significantly improved antitumor efficacy and spared loss of SPAS1-specific CD8+ T cells. Combination treatment also impaired the memory T-cell response, as mice who received combination treatment were compromised for protection from tumor rechallenge. Collectively, these results show that the success of combined immune checkpoint therapies may depend on a potential window of optimal immune response, and that treatment outside this window may trigger regulatory mechanisms that hinder antitumor efficacy.

Pai CS, Huang JT, Lu X, Simons DM, Park C, Chang A, et al. Clonal deletion of tumor-specific T cells by interferon-γ confers therapeutic resistance to combination immune checkpoint blockade. Immunity 2019 Feb 5 [Epub ahead of print].

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