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

Heidi Harjunpää; Stephen J Blake; Elizabeth Ahern; Stacey Allen; Jing Liu; Juming Yan; Viviana Lutzky; Kazuyoshi Takeda; Amy Roman Aguilera; Camille Guillerey; Deepak Mittal; Xian Yang Li; William C Dougall; Mark J Smyth; Michele W L Teng

doi:10.1080/2162402X.2018.1445949

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

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

Authors

Heidi Harjunpää^{1

2}, Stephen J Blake¹, Elizabeth Ahern^{1

3

2

4}, Stacey Allen¹, Jing Liu¹, Juming Yan^{1

2}, Viviana Lutzky³, Kazuyoshi Takeda⁵, Amy Roman Aguilera³, Camille Guillerey^{3

2}, Deepak Mittal^{3

2}, Xian Yang Li³, William C Dougall³, Mark J Smyth^{3

2}, Michele W L Teng^{1

2}

Affiliations

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-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.

Keywords: CD96; PD-1; TIGIT; immune homeostasis; tumor immunity.

Publication types

Research Support, Non-U.S. Gov't