Host Immunity Following Near-Infrared Photoimmunotherapy Is Enhanced with PD-1 Checkpoint Blockade to Eradicate Established Antigenic Tumors

Abstract

Near-infrared photoimmunotherapy (NIR-PIT) induces immunogenic cell death but has mostly failed to induce durable antitumor responses in syngenic tumor mouse models. We hypothesized that adaptive immune resistance could be limiting durable responses after treatmemt with NIR-PIT. We investigated the effects of combining NIR-PIT targeting cell-surface CD44 and PD-1 blockade in multiple syngeneic tumor models. In two of three models, NIR-PIT monotherapy halted tumor growth, enhanced dendritic cell tumor infiltration, and induced de novo tumor antigenspecific T-cell responses absent at baseline. The addition of PD-1 blockade reversed adaptive immune resistance, resulting in both enhanced preexisting tumor antigenspecific T-cell responses and enhanced de novo T-cell responses induced by NIR-PIT. Enhanced immune responses correlated with shared tumor antigen expression, suggesting that antigenicity is a major determinant of response to combination NIR-PIT and PD-1 blockade. Combination treatment induced complete rejection of MC38 tumors treated with NIR-PIT, as well as untreated, distant tumors. Accordingly, tumor antigen-specific T-cell responses were measured in both treated and untreated tumors, validating the development of systemic antitumor immunity. Mice that cleared tumors resisted subsequent tumor challenge, indicating the presence of systemic immune memory. Cumulatively, these results demonstrate reversal of adaptive immune resistance following induction of innate and adaptive immunity by NIR-PIT, resulting in high rates of tumor rejection and/or significant tumor growth control in antigenic syngeneic models of cancer.

The Potential of Nanobody-Targeted Photodynamic Therapy to Trigger Immune Responses

“…We expect that NB-PDT on tumor cells with moderate target expression will lead to more pronounced effects in vivo than in vitro, where tumor vasculature damage also plays a role. It has already been demonstrated that NB-PDT induces extensive tumor damage on a model with moderate expression levels [7] and, in addition, antibody-targeted PDT has been reported to trigger antitumor immunity against tumor cells with moderate levels of target [46]. Another aspect to underline from our study is the moderate immunogenicity induced by the mild NB-PDT condition.…”

Cancer neovasculature-targeted near-infrared photoimmunotherapy (NIR-PIT) for gastric cancer: different mechanisms of phototoxicity compared to cell membrane-targeted NIR-PIT

“…This result suggests that damaging tumor microvasculature in response to DC101-IR700-mediated NIR-PIT might hamper deep-tumor microdistribution of the macromolecules. Moreover, conventional NIR-PIT induces immunogenic cell death (ICD) capable of inducing dendritic cell maturation that drive the differentiation of naïve T cells into effectors [32,33]. On the other hand, it is not unclear that NIR-PIT with DC101-IR700 has the ability to induce ICD, and it might also prevent the infiltration of lymphocytes involved in the immune response that can induce ICD as well as macromolecules.…”

Photodynamic Therapy and Immunity: An Update

“…In a combination study with CD44‐targeted NIR‐PIT and anti‐PD‐1 administration in subcutaneous model of MC38 murine colon carcinoma, Nagaya et al . demonstrated rejection of both treated primary tumor and untreated contralateral tumor, antigen‐specific T‐cell response and resistance to tumor establishment upon rechallenge (116).…”