Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Abstract

: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…The presence of TAMs is frequently associated with the failure of antitumoral treatments, such as chemo- and radiotherapy [ 48 , 49 ]. The resistance to these therapies can be mediated by the release of cytokines from TAMs; in particular, IL-6 has been demonstrated to induce tolerance in the treatment of breast [ 50 ], pancreatic [ 51 ], and colorectal cancer [ 52 , 53 ].…”

“…As a whole, these studies demonstrate that TAMs are essential for the survival and progression of most types of solid tumors [ 85 , 86 , 108 ], and their therapeutic targeting and reprogramming towards an antitumor M1-like phenotype is a promising approach to fight cancer [ 48 , 49 , 109 ].…”

“…In cancer, TAMs therapeutic reprogramming is intended to switch their M2-like protumor properties towards M1-like macrophages, with active defensive activity and antitumor functions, including direct killing of tumor cells, inhibition of angiogenesis, normalization of tumor vessels, and improvement of adaptive immune responses [ 49 ]. Furthermore, TAMs reprogramming in the tumor microenvironment (TME) is also expected to synergize and boost the activity of other antitumoral treatments currently applied in the clinic, such as immune-checkpoint inhibitors (ICIs) or CAR T cells [ 8 ].…”

“…Cancer cells killed by ICD expose calreticulin and other endoplasmic reticulum proteins; they release cytokines and damage-associated molecular patterns (DAMPs), such as ATP or HMGB1, and also tumor antigens, which stimulate antitumor immune responses, resulting in the recruitment and activation of macrophages and T cells to fight against the cancer cells. For other chemotherapeutic drugs, such as gemcitabine, the results are not so clear, and their impact on TAMs’ polarization may depend on the tumor type or on the dose reaching cancer cells [ 49 ]. It was demonstrated that low-dose gemcitabine (GEM) enhances immunogenicity and natural killer (NK) cell-driven tumor immunity in lung cancer [ 112 ].…”

Exploiting Manipulated Small Extracellular Vesicles to Subvert Immunosuppression at the Tumor Microenvironment through Mannose Receptor/CD206 Targeting

“…Immunosuppressive TAMs represent a privileged therapeutic target for the treatment of solid tumors, especially in the case immune checkpoint blockers (ICBs) are used. Given the enormous therapeutic value of TAMs re-education towards M1-like macrophages to promote tumor regression, much attention has focused on effective strategies aimed at targeting TAMs, including the blockade of the M2 phenotype, enhanced activation of M1 macrophages and reprogramming of TAMs toward M1-like phenotype [ 58 , 62 , 63 , 64 , 65 ]. Many of these different approaches against immunosuppressive TAMs have been summarized in Table 1 and strategies directed at TAM reprogramming illustrated in Figure 4 .…”