Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is usually accompanied with a relatively low expression of costimulatory ligands. Keywords: immunology, oncology, tumors Introduction Soft tissue sarcomas (STSs) are a collection of heterogeneous tumors of mesenchymal origin with over 50 different subtypes that can originate from excess fat, muscle, nerves, fibrous, endothelial, or deep skin tissues. of effector memory T cells. These TILs coexpress the immune checkpoints PD1, TIM3, and LAG3 in myxofibrosarcoma and pleomorphic sarcoma, yet TILs coexpressing these checkpoints were near negligible in GIST. Fractions of dominant T-cell clones among STS subtypes were lowest in GIST and liposarcoma, whereas mutational load was relatively low in all STS subtypes. Furthermore, myeloid-derived cells and expression of the costimulatory ligands CD86, ICOS-L and 41BB-L were lowest in GIST when compared with other STS subtypes. Conclusion STS subtypes differ with respect to number and phenotypical indicators of antitumor responsiveness of CD8+ TILs. CD246 Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is usually accompanied with a relatively low expression of costimulatory ligands. Keywords: immunology, oncology, tumors Introduction Soft tissue sarcomas (STSs) are a collection of heterogeneous tumors of mesenchymal origin with over 50 different subtypes that can originate from excess fat, muscle, nerves, fibrous, endothelial, or deep skin tissues. For most patients with non-metastatic STS, standard care of treatment includes surgical resection with or without perioperative (neo)adjuvant chemotherapy or radiotherapy. Depending on the cancer stage and histological subtype, on average, 25%C50% of these patients develop recurrent and/or metastatic disease. The median survival of metastasized STS after treatment by chemotherapy is only 10C15 months.1 2 Therefore, there is an urgent need for novel and effective therapies for the treatment of advanced STS.3 Gastrointestinal stromal tumor (GIST) is different from most STS subtypes, SK1-IN-1 forming a favorable exception. Of these tumors, 85%C90% harbor a mutation in the genes encoding the tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or platelet-derived growth factor receptor , rendering these tumors highly sensitive to the targeted drug imatinib.4 Immune therapies have exhibited therapeutic value in various tumors and have also been tested in STS. Currently, an extending number of studies SK1-IN-1 is exploring the efficacy of different immunotherapeutic treatment strategies in sarcomas.5 6 Interferons (IFNs) (/),7 8 interleukin-2,9 and cancer vaccines have been tested and were reported to induce limited antitumor activity in small fractions of patients with STS.10 Adoptive transfer of NY-ESO1 T-cell receptor (TCR) gene-engineered T cells, however, showed objective responses in 11 out of 18 (61%) patients with NY-ESO1-positive synovial cell sarcoma.11 12 In addition, immune checkpoint antibodies yield objective though variable responses in STS subtypes.13C17 For example, in a study treating patients with various STS subtypes, partial responses were observed for pleomorphic sarcoma, liposarcoma, and synovial sarcoma.18 A recent study, treating a total of 85 patients with various STS subtypes with nivolumab (n=43) or nivolumab plus ipilimumab (n=42), concluded that nivolumab monotherapy does not warrant further study in an unselected STS cohort of patients, given its limited overall efficacy.19 In contrast, in the nivolumab plus ipilimumab group, 6 out of the 38 evaluable patients demonstrated an objective response. Responses were seen in patients with uterine leiomyosarcoma (n=1), non-uterine leiomyosarcoma (n=1), myxofibrosarcoma (n=1), undifferentiated pleomorphic sarcoma or malignant fibrous histiocytoma (n=2), and angiosarcoma (n=1).19 A third study treating various metastasized STS subtypes and bone sarcoma with pembrolizumab (SARC028 trial) reported a 18% objective response rate, with the majority of responses occurring in patients with undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.20 Based on the aforementioned studies, SK1-IN-1 it appears that some STS subtypes respond more often to immune therapies than other subtypes. Interestingly, recent SK1-IN-1 in-depth analysis of the.