Deficiency of host CD96 and PD-1 or TIGIT enhances tumor immunity without significantly compromising immune homeostasis.

Multiple non-redundant immunosuppressive pathways co-exist in the tumor microenvironment and their co-targeting can increase clinical responses. Indeed, concurrent blockade of CTLA-4 and PD-1 in patients with advanced melanoma increased clinical responses over monotherapy alone although the frequency and severity of immune related adverse events (irAEs) also increased. Nevertheless, a substantial number of patients still display an innate resistance phenotype and are unresponsive to current approved immunotherapies even when utilized in combination. In this study, we generated and mice to investigate how loss of CD96 in combination with PD-1 or TIGIT impacts on immune homeostasis and hence the potential of inducing immune related toxicities following co-targeting of these pairs of receptors. The ability of and mice to suppress primary tumor growth was also assessed using the MC38 colon carcinoma and SM1WT1 BRAF-mutated melanoma tumor models. Both or mice displayed no overt perturbations in immune homeostasis over what was previously reported with or mice even when aged for 22 months. Interestingly, increased suppression of subcutaneous tumor growth and complete responses was seen in mice compared to or mice depending upon the tumor model. In contrast, in these models, growth suppression in were similar to or . This enhanced anti-tumor efficacy of appeared to be due to favorable changes in the ratio of CD8 T cells to T regulatory cells or CD11bGR-1 myeloid cells in the tumor microenvironment. Co-targeting CD96 and PD-1 may increase anti-tumor immunity over targeting PD-1 alone and potentially not induce serious immune-related toxicities and thus appears a promising strategy for clinical development.