Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma

Abstract

Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

“…Indeed, several other immune checkpoints were overexpressed, such as IDO1, 72 LAG3, 73 HAVCR2/TIM3, 74 and TIGIT, 75 which represent new targets for new inhibitors under development. In fact, the negative prognostic value of tumor or peri-tumor lymphocyte infiltration in STS has already been reported in several studies, 8,[15][16][17][18][19] but the explanations of this rather counter-intuitive correlation remain to be defined.…”

“…12 Patients with immune deficiencies, such as organ transplant patients, show an increased incidence of sarcomas. 13 Lymphocytic infiltration of the tumor was demonstrated in sarcomas, with positive prognostic value in cutaneous angiosarcomas, 14 negative prognostic value in STS or liposarcomas, 8,[15][16][17][18][19] or no prognostic value in MPNST. 20 An unfavorable prognostic role of tumor-associated macrophages was reported in leiomyosarcomas 21 and myxoid liposarcomas.…”

Development of Checkpoint Inhibitors for Sarcomas

“…39 The presence of TILs and a correlation with prognosis has also been documented in a variety of sarcoma subtypes, including liposarcoma, chordomas, angiosarcomas, synovial sarcoma, and undifferentiated pleomorphic sarcoma (UPS). [40][41][42][43] Another example of the potential activity of immune system against sarcomas results from observations of patients with gastrointestinal stromal tumors (GISTs) treated with imatinib. In addition to the wellcharacterized antitumor effect resulting from tyrosine kinase "on-target" KIT inhibition, benefit from imatinib therapy was associated with increased intratumoral CD8+ T cells, mobilization of natural killer (NK) cells from the stroma into the tumor, and depletion of cells with suppressive functions, through apoptosis of tumor-infiltrating regulatory T cells (Tregs).…”

Possibility of predicting the efficiency of soft tissue sarcoma treatment on the basis of features of their immunological microenvironment

“…Исследования связи клинического те-чения и особенностей локального имму-нитета при саркомах мягких тканей (СМТ) немногочисленны, хотя методы иммуноте-рапии этой патологии активно разрабаты-ваются [6][7][8][9]. Данные опухоли отличаются тяжёлым течением, ранним и нередко мно-гократным рецидивированием, слабой чув-ствительностью к принятым методам лечения, морфологической гетерогенно-стью [10,11].…”

“…Отмеченную в работе W.W. Tsengetal (2014) [8] отрицательную связь присутствия опу-холь-инфильтрирующих лимфоцитов с об-щей и бессобытийной продолжительностью жизни больных липосаркомами авторы свя-зывают с найденной ими гиперэкспрессией рецептора апоптоза PD-1 на CD8…”