Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Sarcoma. 2018; 2018: 9305294.
Published online 2018 Aug 12


Abstract

Sarcoma is comprised of a heterogeneous group of tumors originating from the mesenchyme. Sarcoma is also the first tumor that responded to immunotherapeutic agents often termed as “Coley's toxins.” However, immunotherapy is yet to establish its presence in sarcomas. Complex interactions between tumor and immune cells in the tumor microenvironment play a crucial role in response to immunotherapy. There is a dynamic equilibrium created by the immune cells infiltrating the tumor, and this forms the basis of tumor evasion. Manipulating the intratumoral microenvironment will help overcome tumor evasion.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109466/

Introduction

In this review, we first explore the specific oncogenic alteration characteristics of different subtypes of sarcoma. This is followed by a description of the mechanisms by which tumor infiltrating lymphocytes affect prognosis and the specific immune cell populations that can be targeted and manipulated in different subtypes of sarcoma. We also review the various immune suppressive mechanisms including immune check points, receptors, and tumor-associated macrophages and their relevance in sarcoma. We then focus on intratumoral immunotherapy, mechanisms of immune interactions, limitations, and the types of intratumoral therapies including oncolytic viruses, immune cells, and cytokines. We foresee intratumoral immunotherapies being able to target and influence management of sarcomas in the future.

Soft tissue sarcomas arise from cells of mesenchymal lineage, including muscle, fat, blood vessel, and nerve. Over 50 histological types have been identified. Localized tumors are usually well controlled with surgery. Localized tumors that have high-grade histologies and those are over 5 cm, however, have over a 50% risk of recurrence. Patients with high-risk localized tumors are usually treated with combinations of surgery, radiation, and/or chemotherapy. These approaches have failed to substantially improve overall survival. Chemotherapy has not significantly impacted the outcome of patients with metastatic soft tissue sarcoma. The prognosis of these patients is very poor. Median overall survival is 8 to 12 months [1].

Immunotherapy has been an attractive approach to treat refractory cancers. Sarcoma is considered to be the first cancer for which immunotherapy was effectively applied. Based on observations of tumor regressions in patients with concomitant streptococcal infections, William B. Coley injected streptococcal organisms into tumors, especially sarcomas, in the last decade of the 19th century [2]. Over 50% of the inoperable sarcoma patients who are Coley treated were reported to respond completely. Furthermore, approximately 20% survived over 20 years [2]. With their poorly characterized preparation and unpredictable toxicities, “Coley's toxins” never became clinically useful. Immunotherapeutic approaches have been tested in patients with soft tissue sarcoma. The results have not been as spectacular as some of the other solid tumors. Immune checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) is leading to durable clinical responses in an increasing number of cancers. However, responses in patients with soft tissue sarcoma have been infrequent [3–6].

[*]Immunotherapy response is dependent on complex interactions between tumor and immune cells within the tumor microenvironment. Several factors determine whether or not immunotherapy response will be promoted or inhibited. These include the inherent antigenicity of the tumor. Mutations in proteins and/or aberrant proteins expressed by tumor cells and the “neoantigens” they generate are the primary targets for T-cell-mediated destruction. Tumor mutation burden has emerged as a quantitative marker that can help predict responses to immune checkpoint inhibition across different cancers. Immunotherapy response is also dependent on the infiltration into tumor of immune effector cells. Specific patterns of tumor infiltrating lymphocytes (TILs) within the tumor microenvironment are associated with improved outcome in patients with many types of cancers, regardless of the type of therapy administered. Most importantly, a variety of processes within the microenvironment can suppress interactions between tumors and immune effector cells and promote the escape of tumors from immune surveillance. Immune checkpoint ligands and receptors have emerged as the major targetable mechanism of tumor immune escape. Several other molecular, soluble, and cellular factors are involved, and whether or not these factors are being addressed will also determine immunotherapy sensitivity.

Understanding the soft tissue sarcoma microenvironment is not only critical relative to improving the efficiency of current immunotherapies but also for the development of more effective approaches. In this review, we focus on the recent advances made in understanding the immune microenvironment in soft tissue sarcoma. We also discuss the rationale for building upon Coley's work and directly modifying the soft tissue sarcoma microenvironment using the intratumoral administration of immunologically active agents.

Abstract

Two seemingly incompatible models exist to explain the progression of cancers in immunocompetent hosts. The cancer immunosurveillance hypothesis posits that recognition of transformed cells by the immune system results in the generation of an effector response that may impede tumor growth. Clinically detectable cancer results from the emergence of tumor variants that escape this selective pressure. Alternatively, induction of immune tolerance to tumor antigens may enable cancer progression. We established a model where changes in the function of tumor-specific T cells and in tumor antigen expression could be followed during cancer progression. Early recognition of antigen led to activation, expansion, and effector function in tumor-specific CD4+ T cells resulting in the outgrowth of tumors expressing substantially reduced levels of antigen. Antigen loss was not complete, however, and levels remained above the threshold required for tumor-specific T cell recognition in vivo. In the face of persisting antigen, T cell tolerance ensued, leading to an impaired ability to mediate further antigen loss. Together, these studies establish that the processes of immunosurveillance and tumor editing coexist with a process in which the functional tumor-specific T cell repertoire is also “edited,” reconciling two hypotheses historically central to our attempts to understand host antitumor immunity.

Keywords: immunosurveillance, immunoediting, immune tolerance, T lymphocyte, tumor escape
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211996/

Introduction

The role played by host immunity on the development and progression of cancer has been a subject of speculation and experimentation for over 50 yr (1–3). In animal models, deficiencies in both innate and adaptive immunity have been associated with an increased incidence and accelerated kinetics of tumor development induced by carcinogens, transgenic expression of oncogenes, or even of cancers that arise spontaneously (4, 5). These results support the hypothesis that the normal immune system plays a physiologic role in surveying for events associated with malignant transformation of host tissues. In immunocompetent mice, immune-mediated antitumor effector responses have been demonstrated in the early phases of tumor growth. In mice with established tumor, such responses are even capable of rejecting a small challenge of the same cancer type injected at a distant anatomical site—so called “concomitant immunity” (6). The identification of tumor escape variants that have lost expression of dominant antigens, have altered antigen processing machinery, or have lost components required for sensitivity to immune-mediated killing is compatible with successful evasion of immunologic selective pressure, a process termed “immunoediting” by Schreiber and colleagues (5). Consistent with this picture of tumor progression requiring adaptation and selection by host immunity, tumors arising in immunodeficient animals (i.e., “unedited” tumors) are frequently rejected when transplanted into syngeneic, immunocompetent recipients but not when implanted into secondary immunodeficient hosts (4).

Whereas expanded tumor-specific T cell populations can often be detected in the blood or tumors of cancer patients, consistent with host immunosurveillance, not infrequently, cancer cells isolated from progressing tumors can still be recognized by these T cells after their in vitro activation and expansion. These findings suggest that selection of less antigenic or immunogenic tumor subclones cannot be the sole mechanism involved in tumor evasion of host immunity. In fact, even though clonal expansion of tumor-specific T cells is sometimes demonstrated in vivo, such cells have often been shown to have impaired functional responses to antigen, especially when studied after minimal manipulation (7). Mouse models have also demonstrated that although early recognition of tumor antigen leads to clonal expansion of tumor-specific T cells, such cells have impaired responses to antigen in vitro, and their ability to be primed in vivo is substantially diminished compared with mice with established tumor not expressing the relevant antigen, or to mice without tumor (8–10). These observations have led to the argument that tumor progression is accompanied by the development of tumor antigen–specific T cell tolerance, perhaps through mechanisms akin to those that regulate responses to normal self-antigens (11). Together, these results support the hypothesis that the development of tumor-specific T cell tolerance is a key event in the course of tumor progression. From the perspective of a “failed” host response to tumor, it would appear that the ultimate outcome of an antigenic encounter by tumor-specific T cells is the induction of specific unresponsiveness—a conclusion seemingly at odds with the tenor of the immune surveillance hypothesis.

To more fully examine the immunological events that accompany tumor progression, we established a model that employs a defined antigen and a defined population of antigen-specific T cells. By fixing these two parameters, serial quantitative measurements of tumor antigenicity and tumor-specific T cell function could be made in a single system during tumor progression. This analysis demonstrated that the initial recognition of an immunogenic tumor by tumor-specific CD4+ T cells led to their activation, expansion, and acquisition of effector function capable of selecting for the outgrowth of tumors with substantially reduced levels of antigen expression. However, antigen loss was not complete and levels presented to the immune system by edited tumor remained above the threshold required for recognition by tumor-specific T cells in vivo. In the face of this persistent exposure to antigen, T cell effector function waned, leading to T cell tolerance, and these tumor antigen–experienced T cells were no longer capable of exerting selective pressure sufficient for mediating tumor antigen loss. Together, these studies establish that cancer progression involves reciprocal changes in the antigenic profile of the evolving tumor and in the functional capacity of the tumor antigen–specific T cells. These changes result in a homeostasis in which a less immunogenic tumor emerges in the face of an immune system less capable of responding to it.