Author:

Abstract:

Therapeutic targeting of immune cell surface-tethered immune-checkpoints that inhibit anti-cancer immunity, via antibodies-based immune-checkpoint blockers (ICBs), has revolutionized the clinical oncological practice in recent years. Regrettably, only a subset of cancer patients tend to respond to these ICBs. Biomarker-guided, multimodal therapeutic regimen, are predicted to vastly improve the clinical efficacy of ICBs. Therein, one of the current strategies entails combinatorial application of ICBs targeting cytotoxic T-lymphocyte-associated protein (CTLA4) or, programmed cell death protein 1 (PD1)/programmed death ligand 1 (PD-L1), following cytotoxic (i.e. cell death) chemo or targeted therapies. However, currently this strategy is not entirely accounting for the potential 'skewing' effects of cancer cell death on immune-checkpoint landscape since dying cancer cells may engage, or facilitate, inhibitory immune-checkpoints on immune cells in a manner not entirely predictable. This unpredictability arises from the poorly deciphered role of immune checkpoints in interactions with dying cancer cells. Such skewing may favor novel 'alternative' immune-checkpoints - a notion supported by our patient tumor transcriptome analyses. A 'switch' to alternative immune-checkpoints can negatively affect the efficacy of ICBs targeting conventional immune-checkpoints like CTLA4, PD1/PD-L1. Thus, systematically studying this aspect is vital for designing 'smart' multimodal therapies wherein ICBs are "matched" to the immune-checkpoints preferentially engaged by dying cancer cells. Hence, this project aims to decipher the cross talk between therapy-induced cancer cell death and immune-checkpoints; and study its immunological implications, to create an effective combinatorial immunotherapy regimen.