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Oncoimmunology. 2018 Mar 26;7(7):e1445949. doi: 10.1080/2162402X.2018.1445949. eCollection 2018.

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

Author information

1
Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
2
School of Medicine, The University of Queensland, Herston, Queensland, Australia.
3
Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
4
Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
5
Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

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

KEYWORDS:

CD96; PD-1; TIGIT; immune homeostasis; tumor immunity

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