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 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.

TIGIT as an emerging immune checkpoint

“…Five clinical trials are currently evaluating the safety of TIGIT/PD‐1 co‐blockade in cancer patients. Other promising combination targets for TIGIT include TIM‐3 , CD112R or CD96 . Interestingly, while most efforts are focused on blocking TIGIT inhibitory activity through mAbs, a recent study considered TIGIT in the context of T cell engineering .…”

“…The majority of patients treated with ipilimumab (anti‐CTLA‐4 mAb) showed irAEs with any grade, while patients treated with PD‐1 blockade showed fewer and less severe irAEs compared to CTLA‐4 blockade . Contrary to CTLA4 −/− mice or to Pdcd1 −/− mice, which develop severe autoimmune and lymphoproliferative syndromes , mice deficient for TIGIT show no signs of spontaneous autoimmunity nor defects in the development of haematopoietic cells . However, when TIGIT −/− mice are immunized or crossed with an autoimmune‐prone strain, they show enhanced development of autoimmune disease .…”

“…TIGIT has emerged as a particularly attractive target for cancer therapy due to its seemingly central role in limiting anti‐tumour responses. Moreover, experiments using TIGIT −/− mice suggested that targeting TIGIT would be safe, and possibly trigger fewer irAEs than anti‐PD‐1 or anti‐CTLA‐4 mAbs . Here, we review our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.…”

Targeting PVR (CD155) and its receptors in anti-tumor therapy

“…Similar findings were recently confirmed in double knockout mice lacking both PD-1 and CD96. 145 Moreover, indirect evidence supporting the enhanced anti-tumor performance when both PVR receptors are targeted has been published. TIGIT knockout mice exhibit less metastasis when treated with an anti-CD96 mAb than equivalently treated wild-type mice, indicating that either distinct mechanism or different lymphocyte subsets are involved in this control, 48 although this finding was not confirmed in double knockout mice.…”

“…TIGIT knockout mice exhibit less metastasis when treated with an anti-CD96 mAb than equivalently treated wild-type mice, indicating that either distinct mechanism or different lymphocyte subsets are involved in this control, 48 although this finding was not confirmed in double knockout mice. 145 However, most of the studies did not adequately address the role of the CD96-PVR interaction and the mechanism of action of these antibodies. As shown in a recent study by Aquilera et al, 92 a specific anti-CD96 antibody that binds to second Ig domain of CD96 and does not prevent its interaction with PVR still retains NK cell-mediated antimetastatic activity in several murine melanoma models.…”