Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness

Abstract

Sarcomas are uncommon malignancies of mesenchymal origin that can arise throughout the human lifespan, at any part of the body. Surgery remains the optimal treatment modality whilst response to conventional treatments, such as chemotherapy and radiation, is minimal. Immunotherapy has emerged as a novel approach to treat different cancer types but efficacy in soft tissue sarcoma and bone sarcoma is limited to distinct subtypes. Growing evidence shows that cancer-stroma cell interactions and their microenvironment play a key role in the effectiveness of immunotherapy. However, the pathophysiological and immunological properties of the sarcoma tumor microenvironment in relation to immunotherapy advances, has not been broadly reviewed. Here, we provide an up-to-date overview of the different immunotherapy modalities as potential treatments for sarcoma, identify barriers posed by the sarcoma microenvironment to immunotherapy, highlight their relevance for impeding effectiveness, and suggest mechanisms to overcome these barriers.

Keywords: hypoxia; immunosuppression; mechanotherapeutics; tumor microenvironment; tumor normalization.

Figure 1

Landscape of immunotherapy application in sarcoma treatment. Visualization of the number of studies performed from 2011 to 2021 for each sarcoma subtype, assessing the efficacy of different immunotherapy modalities in the preclinical setting. The circle diameter indicates the relative proportion of preclinical studies identified. Combination circle includes combinations between two or more immunotherapy modalities or combinations with chemotherapeutics or radiation therapy. The data included in this figure are listed in Tables 2 and 3 and Tables S1 and S2. FB, fibrosarcoma; DDLPS, dedifferentiated liposarcoma; LPS, liposarcoma; RMS, rhabdomyosarcoma; LMS, leiomyosarcoma; SS, synovial sarcoma; UPS, undifferentiated pleomorphic sarcoma; Other STS, undefined type of STS; EwS, Ewing sarcoma; BS, bone sarcoma; CHS, chondrosarcoma; ICI, immune checkpoint inhibitors; ACT, adoptive cell therapy; iSVs, in situ vaccines

Figure 2

A. Immune phenotypes of solid tumors and normalization strategies. Based on the spatial distribution of CD8⁺ T lymphocytes in the TME, solid tumors are classified into highly inflamed- “hot” and non-inflamed- “cold”. “Cold” tumors like Ewing sarcoma can be further subdivided into immune desert or immune excluded. In “hot” tumors like most soft tissue sarcomas and osteosarcoma, T cells are present but inactive or exhausted. TME of “hot” tumors is defined by PD-1⁺ T cells and PD-L1⁺ tumor cells and macrophages, a high degree of tumor mutational burden and generally correlates with good response to ICI. In the immune desert phenotype, immune cells are absent from the tumor and its periphery while in the immune-excluded phenotype, immune cells accumulate at the periphery and do not efficiently infiltrate tumor bed. B. These three immune phenotypes can be reverted by TME normalization. TME normalization can be achieved by normalization of the tumor vasculature through targeting of angiogenic factors (such as VEGF and/or angiopoietin-2) and/or immune checkpoints (PD-L1, PD-1) and by normalization of the tumor ECM including reprogramming of CAFs to reduce fibrosis. These two normalization strategies either alone or in combination improve vessel perfusion, oxygen delivery, infiltration and activation of T cells and drug distribution.

Figure 3

TME normalization strategies affect immune phenotype and responsiveness to treatment. In the immune desert phenotype (blue shading) the lack CTL in tumor parenchyma permits cancer cells to grow uninterruptedly favoring immunological ignorance (a lack of antigens and/or their presentation- step 1 and 2), tolerance (a lack of response to antigen presentation) and a lack of T cell priming (step 3). Accordingly, immune desert tumors are the least responsive to ICI. Under such conditions, vascular normalization improves the delivery of nanomedicine and increases immunogenic cell death and thereby release of tumor cell antigens and promotes antigen presentation through DC maturation. In tumors of the immune excluded phenotype (purple shading), T cells fail to penetrate tumor bed and are limited to the periphery. Penetration of T cells is primarily impeded by immature or compressed vessel and density of extravascular matrix and CAF-induced fibrosis. In addition, angiogenic signaling dysregulates the expression of adhesion molecules on the vessel wall, thereby reducing the extent of leukocyte binding and limiting their flux into tumors while hypoxia contributes to the establishment of immunosuppressive T cells like Tregs. Thus, TME normalization in immune excluded phenotypes improves tumor oxygenation, delivery drugs and makes the tumor stroma accessible to T cells (step 4 and 5). The immune inflamed TME (pink shading) is infiltrated by immune cells which have reduced antitumor activity due to various inhibitory factors, which are often induced by hypoxia (step 6 and 7). This phenotype has the most potential for sensitivity to ICI. Normalization strategies targeting VEGF signaling can be employed to restrict the recruitment of immunosuppressive immune cells like M2-like macrophages, Tregs and MDSC, while targeting of hypoxia will suppress immune checkpoint signaling allowing cancer cells to be recognized and killed by CTLs (step 6 and 7). Thus, selecting the type of normalization strategy (center, dashed red circle) based on the immunological properties of tumor can specifically enhance each step of cancer immunity cycle allowing its continuity.