Resistance to Anticancer Immunity in Cancer Patients

Potential Strategies To Reverse Resistance

B. Bonavida; S. Chouaib


Ann Oncol. 2017;28(3):457-467. 

In This Article

Abstract and Introduction


In the 1990s, the application of immunotherapy approaches to target cancer cells resulted in significant clinical responses in patients with advanced malignancies who were refractory to conventional therapies. While early immunotherapeutics were focused on T cell-mediated cytotoxic activity, subsequent efforts were centered on targeted antibody-mediated anticancer therapy. The initial success with antibody therapy encouraged further studies and, consequently, there are now more than 25 FDA-approved antibodies directed against a range of targets. Although both T cell and antibody therapies continue to result in significant clinical responses with minimal toxicity, a significant subset of patients does not respond to immunotherapy and another subset develops resistance following an initial response. This review is focused on describing examples showing that cancer resistance to immunotherapies indeed occurs. In addition, it reviews the mechanisms being used to overcome the resistance to immunotherapies by targeting the tumor cell directly and/or the tumor microenvironment.


While conventional cancer treatments, such as surgery, chemotherapy, and radiation have extended survival for many patients, they have had limited success in certain tumor types and in patients with late stage diseases. Consequently, the search for more effective and less toxic cancer therapeutics continues. For many years, researchers have explored the idea that the immune system could be harnessed with the aim of inducing an anti-tumor immune response. It has been recognized that tumors are often poorly immunogenic for both humoral antibody and T cell-mediated responses. Several mechanisms have been characterized that alter the immune responses to tumors,[1] including immune editing,[2] tumor-derived suppressor factors,[3] suppressor factors derived from the tumor microenvironment (TME),[4,5] the induction of suppressor T-cells[3] and the development of myeloid-derived suppressor cells (MDSCs).[6]

The innate immune system plays a role in the initial anti-tumor response and, as such, it has been considered as a therapeutic target. However, in the majority of cases, when the tumor develops mechanisms of resistance to cell death, both the innate and adaptive immune responses become ineffective and are unable to eradicate the tumor. Interestingly, a deeper understanding of these mechanisms is providing new means to circumvent or alter the resistance of the immune response to tumors. Consequently, immunotherapy has emerged as a significant therapeutic strategy in the eradication of many tumor types.

The role of the immune system in the regression of tumors was first highlighted by the FDA-approved administration of IL-2 in renal cancer in 1992 and in metastatic melanoma in 1998.[7] This was followed by the use of ex vivo IL-2 to generate and expand autologous T-cells and tumor infiltrating lymphocytes (TILs) for adoptive T-cell (ATC) transfer and treatment of cancer patients. ATC has shown promising results in the treatment of advanced cancer and, in particular, for a subset of patients refractory to standard therapy.[8–12] These findings, while not applicable to all tumors, led to the development of novel methods to introduce anti-tumor TCRs into autologous lymphocytes and the engineering of tumor-specific chimeric antigen receptors (CARs) into normal lymphocytes for therapeutic use.[8,13–15]

During the last two decades, in addition to cell-mediated immunotherapy, we have also seen the emergence of antibody-mediated targeted therapies directed against tumor cells or their microenvironment. The first chimeric monoclonal antibody (mAb), rituximab (anti-CD20 mAb), was FDA-approved in 1997 for the treatment of low grade and follicular NHL.[16,17] Subsequently, over 25 mAbs have been approved for the treatment of a variety of cancers.[18–20]

Although the advent of new immunotherapy approaches has improved the survival of many patients with advanced malignancies, the prevalence of non-responders, especially in common malignancies such as breast, colon and prostate cancers, also provides a strong reminder that we possess only a partial understanding of the events underlying the immune resistance of tumors. It should be noted that the success of preclinical studies in mice contrasts with the current situation in the clinic.[21–24]The ultimate goal of most T cell-mediated anti-cancer immunotherapy strategies is to induce a strong cytotoxic T lymphocyte (CTL) response, with the prevailing view being that induced CTLs will eradicate tumor cells. However, this view has been challenged by clinical observations showing that even a strong and sustained cytotoxic response may only translate to a partial response in patients. This is due to a number of complex issues, such as an unfavorable TME (resulting in impaired lymphocyte migration and recruitment), tumor evasion, immune editing, and selection of immuno-resistant tumor cell variants.[25] In addition, regulatory T cells (Tregs), macrophages, MSDCs, and neutrophils constitute major components of the immune infiltrate within the tumor tissue that curtails anti-tumor immunity.[26] A better understanding of the underlying molecular mechanisms of tumor escape remains a vital step in the development of strategies to overcome this process.

Several novel strategies have been successfully used in the reversal of resistance including checkpoint inhibitors, new monoclonal antibody-drug conjugates (ADCs), engineered T cells, agents targeting the TME, combination therapies and immunosensitizing agents, among others. Accumulating evidence indicates that immunosurveillance represents only one dimension of the complex relationship between the immune system and cancer.[27] It has become clear that the host immune system is involved in both eliminating tumors and sculpting the immunogenic phenotypes of tumors that eventually form in immunocompetent hosts, indicating that immunity plays a dual role in the complex interactions between tumors and the host. In fact, the immune system can suppress tumor growth by destroying cancer cells but can also promote tumor progression by establishing conditions within the TME that facilitate tumor outgrowth.

Resistance to immunotherapy strategies in various cancers has been the subject of numerous recent reviews with little discussion concerning whether this resistance is a dogma or a proven phenomenon.[28,29] This review focuses on the recent approaches that have been used to overcome resistance by manipulating the effector cells and antibodies that are directed to the tumor cells or to the TME.