Abstract
Immunotherapy has emerged as a promising and effective treatment for cancer, yet the clinical benefit is still variable, in part due to insufficient accumulation of immune effector cells in the tumour microenvironment. Better understanding of tumour-infiltrating lymphocytes (TILs) from nonhuman primate tumours could provide insights into improving effector cell accumulation in tumour tissues during immunotherapy. Here, we characterize TILs in a cynomolgus macaque tumour model in which the tumours were infiltrated with CD4+ and CD8+ T cells and were eventually rejected. The majority of CD4+ and CD8+ TILs exhibited a CD45RA−CCR7− effector memory phenotype, but unlike circulating T cells, they expressed CD69, a marker for tissue-resident memory T (TRM) cells. CD69-expressing CD8+ TILs expressed high levels of the cytotoxic molecule granzyme B and the co-inhibitory receptor PD-1. Consistent with the TRM cell phenotype, CD8+ TILs minimally expressed CX3CR1 but expressed CXCR3 at higher levels than circulating CD8+ T cells. Meanwhile, CXCL9, CXCL10 and CXCL11, chemokine ligands for CXCR3, were expressed at high levels in the tumours, thus attracting CXCR3+CD8+ T cells. These results indicate that tumour-transplanted macaques can be a useful preclinical model for studying and optimizing T cell accumulation in tumours for the development of new immunotherapies.
Highlights
Www.nature.com/scientificreports of distinct steps that include rolling, adhesion, extravasation and migration within the tissue[11]
We showed that a nonhuman primate tumour model, in which induced pluripotent stem cell (iPSC)-derived tumour cells were transplanted into major histocompatibility complex (MHC)-matched macaques, represents a useful animal model for studying TILs
Chemokine– chemokine receptor expression profiles in TILs and tumour locales in this macaque model share many features with those reported for human cancers, rendering this model useful for preclinical studies that aim to optimize immune effector cell trafficking to the tumour site
Summary
Www.nature.com/scientificreports of distinct steps that include rolling, adhesion, extravasation and migration within the tissue[11]. We previously established a novel tumour transplantation model in cynomolgus macaques, in which induced pluripotent stem cell (iPSC)–derived tumour cells carrying a homozygous major histocompatibility complex (MHC) haplotype were injected into MHC-matched macaques[18]. These cells formed tumours when injected into immunodeficient NOG mice, they were immunologically rejected in MHC-matched macaques within 4–5 weeks. CD8+ TILs that accumulated at the tumour site had TRM-like phenotypes and expressed high levels of CXCR3, and the tumour expressed CXCR3 ligands, mirroring the characteristics of TILs in human cancers This macaque model proves useful for analysing and optimizing T cell trafficking and localization to the tumour site in the development of new immunotherapies
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