Abstract 103P
Background
Single agent anti-PD1 therapy has shown limited clinical benefit in liposarcoma (LS). The MDACC-led study (NCT02815995), which combined anti-CTLA4 and anti-PDL1 across multiple soft-tissue sarcomas, showed increased expression of CD73 in T cells on treatment. CD73 is related to immunosuppression, reduced antitumoral responses, immune therapy resistance and metastasis. However, on T cells, CD73 induces long-lived memory properties, higher proliferation and survival or the reduction of effector capacity and survival depending on the activation state. Understanding the biology of this receptor will support the rational use of CD73 blockade therapy in LS.
Methods
Resected LS samples (well-differentiated (WDLS) and de-differentiated (DDLS)) were divided for phenotyping by flow cytometry, TIL expansion, adenosine quantification and cytokines. Phenotypic analysis included: CD73, A2aR, PD-1, Tim3, CTLA-4, LAG3, OX40, ICOS and 41BB. Expanded TIL were assessed for cytotoxicity by IFNg production and metabolic state (ROS, mitochondrial activity) by flow cytometry.
Results
The frequency of CD45+ cells (n=47, 0-89.60%) varied. T cell subsets from WDLS express higher CD73 compared to DDLS (p=0.0017 for CD4+ TIL and 0.0049 for CD8+ TIL). CD73 expression was observed in CD4 and CD8 TIL, irrespective of PD-1 co-expression. Adenosine levels were highly variable (0-84.05 nmol/g tissue) and did not correlate with TIL phenotype or tissue cytokines. Tumors were rich in growth and survival factors and chemokines but lacked a correlation with LS subtypes or TIL phenotypes. TIL expansion success was 48% (n=25 cases). The frequency of CD8+CD73+ TIL were significantly higher in cases with successful TIL expansion (p=0.049) and was highest in those expanded from WDLS cases. IFN-g production from expanded TIL was related to intrinsic metabolic profiles associated with mitochondrial mass and ROS production.
Conclusions
LS exhibited an immunosuppressive environment linked to high PD-1 expression and a diverse cytokine landscape. CD73 expression and co-expression with PD-1 differed between WDLS and DDLS, suggesting a differential impact of anti-CD73 on TIL. We hypothesize that CD73 expression on CD8+ T cells may identify more functional, less exhausted TIL.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Generous donation by the William Oates family.
Disclosure
N. Somaiah: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Epizyme, Aadi Biosciences. C. Haymaker: Financial Interests, Personal, Other, Participation in an advisory working group: Nanobiotix; Financial Interests, Personal, Other, Session Chair: Society for Immunotherapy of Cancer; Financial Interests, Personal, Other, Stock options as a member of the Scientific Advisory Board: Briacell; Financial Interests, Institutional, Research Grant, Research funding provided to institution: Iovance; Financial Interests, Institutional, Research Grant: Dragonfly, BTG, Sanofi; Non-Financial Interests, Personal, Advisory Role, Member of the SAB: Mesothelioma Applied Research Foundation. All other authors have declared no conflicts of interest.