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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.

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


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.


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

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