Cancer‐testis antigens in canine histiocytic sarcoma and other malignancies

Abstract

Cancer‐testis antigens (CTAs) are a category of self proteins aberrantly expressed in diverse malignancies, mostly solid tumours, due to epigenetic de‐repression. Normally expressed only in fetal or gametogenic tissues, CTAs are tantalizing immunotherapy targets, since autoimmunity risks appear minimal. Few prevalent CTAs have been identified in human hematologic cancers, and just two in their veterinary counterparts. We sought to discover new CTAs in canine hematologic cancers such as histiocytic sarcoma (HS) and lymphoma to foster immunotherapy development. To accomplish this, the ligandome binding the dog leukocyte antigen (DLA)‐88*508:01 class I allele overexpressed in an HS line was searched by mass spectrometry to identify possible CTA‐derived peptides, which could serve as CD8+ T‐cell epitopes. Twenty‐two peptides mapped to 5 human CTAs and 12 additional proteins with CTA characteristics. Expression of five promising candidates was then evaluated in tumour and normal tissue by quantitative and end‐point RT‐PCR. The ortholog of an established CTA, IGF2BP3, had unexpectedly high expression in peripheral blood mononuclear cells (PBMCs). Four other testis‐enhanced proteins were also assessed. AKR1E2, SPECC1 and TPX2 were expressed variably in HS and T‐cell lymphoma biopsies, but also at high levels in critical tissues, including kidney, brain and marrow, diminishing their utility. A more tissue‐restricted candidate, NT5C1B, was detected in T‐cell lymphomas, but also at low levels in some normal dog tissues. These results illustrate the feasibility of discovering canine CTAs by a reverse approach, proceeding from identification of MHC class I‐presented peptides to a comparative RNA expression survey of tumours and normal tissues.

Sarcomas—A barren immunological wasteland or field of opportunity for immunotherapy?

“…More recently NY‐ESO‐1 has also been detected in the vast majority of human liposarcoma samples in two distinct studies 47,48 . In canine HS and STS, Nemec and coworkers identified several putative CTs, however, none of these antigens appeared to be as promising a target as NY‐ESO‐1 is for certain human sarcomas 49 . This work highlights the potential species restrictions of CT antigens.…”

“…47,48 In canine HS and STS, Nemec and coworkers identified several putative CTs, however, none of these antigens appeared to be as promising a target as NY-ESO-1 is for certain human sarcomas. 49 This work highlights the potential species restrictions of CT antigens. Further, this suggests the need for ongoing screening to find candidate antigens that may be safely targeted in veterinary oncology and further prioritized for therapeutic targeting as seen in human oncology.…”

“…66 nately, these peptides were also expressed in normal and critical tissues, reducing their use as immunotherapeutic targets. 49 Countering the potential immunogenicity of these tumours, expression of the checkpoint molecule CTLA-4 was increased in circulating CD4+ and CD8+ T cells in dogs with HS, and PD-1 expression was increased in circulating CD8+ cells. 68 PD-L1 has also been detected in canine HS cell lines and primary tumour biopsy material, and its expression is further up-regulated by IFNγ.…”

“…Eluting peptides from a histiocytic sarcoma that over‐expressed DLA‐88*508:01, Nemec et al identified five peptides that mapped to human CT antigens and 12 additional peptides with CT characteristics. Unfortunately, these peptides were also expressed in normal and critical tissues, reducing their use as immunotherapeutic targets 49 . Countering the potential immunogenicity of these tumours, expression of the checkpoint molecule CTLA‐4 was increased in circulating CD4+ and CD8+ T cells in dogs with HS, and PD‐1 expression was increased in circulating CD8+ cells 68 .…”

The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop

“…For example, Kcnd2, Tspan12, Ing3 and Cped1 located on Chromosome six are known to promote proliferation of breast cancer cells ( Yang et al, 2023 ), be a critical factor for cancer associated fibroblast mediated invasion ( Otomo et al, 2014 ), used as a potential biomarker for CRC/breast cancer ( Kim and Lee, 2022 ; Li et al, 2023 ) or confer oncogenic effects in prostate cancer ( Zhu et al, 2023 ) respectively. Likewise on chromosome 12, expression of Matn3, Osr1, and Nt5c1b have been associated with colon adenocarcinoma, gastric and breast cancer development ( Zhao Z. et al, 2023a ; Chi et al, 2023 ; Gadwal et al, 2023 ); potential use as a biomarker for breast cancer ( Li et al, 2020 ) or promotion of EMT and metastasis in breast cancer ( Wang et al, 2020 ; Li et al, 2021 ) and identified as a cancer testis-antigen in canine malignancies ( Nemec et al, 2019 ) respectively. On the X chromosome, Il13ra1, Pgrmc1, Septin6, Ndufa1, Nkrf, Zcchc12, Lonrf3, Slc25a5, Ct47 and Dock11 have been associated with numerous cancers including: breast cancer ( Park et al, 2017 ; Zhao Y. et al, 2023 ), basal cell carcinoma ( Mamelak et al, 2005 ), glioblastoma multiforme ( Han and Puri, 2018 ), gastric cancer ( Li et al, 2019 ), hepatocellular carcinoma ( Fan et al, 2021 ), lung cancer ( Lu et al, 2023 ), neuroblastoma ( Seneviratne et al, 2023 ), osteosarcoma ( Cui and Dong, 2022 ), ovarian serous cystadenocarcinoma ( Zhang et al, 2018 ), pancreatic cancer ( Feng et al, 2021 ; Shi et al, 2022 ), papillary thyroid cancer ( Wang et al, 2017 ) and T-cell acute lymphoblastic leukemia ( Lahera et al, 2023 ).…”