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

Abstract

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 <i>Pdcd1^-^/^-CD96^-^/^-</i> and <i>Tigit^-^/^-CD96^-^/-</i> 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 <i>Pdcd1^-^/^-CD96^-^/^-</i> and <i>Tigit^-^/^-CD96^-^/-</i> mice to suppress primary tumor growth was also assessed using the MC38 colon carcinoma and SM1WT1 BRAF-mutated melanoma tumor models. Both <i>Pdcd1^-^/^-CD96^-^/^-</i> or <i>Tigit^-^/^-CD96^-^/-</i> mice displayed no overt perturbations in immune homeostasis over what was previously reported with <i>Pdcd1^-^/^-</i> or <i>Tigit^-^/^-</i> mice even when aged for 22 months. Interestingly, increased suppression of subcutaneous tumor growth and complete responses was seen in <i>Pdcd1^-^/^-CD96^-^/^-</i> mice compared to <i>Pdcd1^-^/^-</i> or <i>CD96^-^/^-</i> mice depending upon the tumor model. In contrast, in these models, growth suppression in <i>Tigit^-^/^-CD96^-^/^-</i> were similar to <i>Tigit^-^/^-</i> or <i>CD96^-^/^-</i> . This enhanced anti-tumor efficacy of <i>Pdcd1^-^/^-CD96^-^/^-</i> appeared to be due to favorable changes in the ratio of CD8⁺ T cells to T regulatory cells or CD11b⁺GR-1^hi 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.