CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy

Rodríguez-García, Alba; Lynn, Rachel C.; Poussin, Mathilde; Eiva, Monika A.; Shaw, Lauren; O’Connor, Roddy S.; Minutolo, Nicholas G.; Casado‐Medrano, Victoria; López, Gonzalo; Matsuyama, Tomohiko; Powell, Daniel J.

doi:10.1038/s41467-021-20893-2

Cited by 198 publications

(155 citation statements)

References 102 publications

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“…In this regard, therapeutic strategies against immunosuppressive populations (e.g., tumor-associated macrophages, Tregs etc. ), leukemia-supporting molecules expressed by stroma cells, altered cytokine networks and immune checkpoint signals are under investigation in several solid and hematological malignancies [ 136 , 137 ]. At this purpose, chimeric receptor antigen (CAR)-T cells, antibodies against developmental pathways (e.g., anti-CSF1R antibody) [ 111 ], neutralizing antibodies for soluble factors [ 44 ] (e.g., inflammatory cytokines, BMP4, Activin A etc.)…”

Section: Resultsmentioning

confidence: 99%

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

Dander

Palmi

D’Amico

et al. 2021

IJMS

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Genetic lesions predisposing to pediatric B-cell acute lymphoblastic leukemia (B-ALL) arise in utero, generating a clinically silent pre-leukemic phase. We here reviewed the role of the surrounding bone marrow (BM) microenvironment in the persistence and transformation of pre-leukemic clones into fully leukemic cells. In this context, inflammation has been highlighted as a crucial microenvironmental stimulus able to promote genetic instability, leading to the disease manifestation. Moreover, we focused on the cross-talk between the bulk of leukemic cells with the surrounding microenvironment, which creates a “corrupted” BM malignant niche, unfavorable for healthy hematopoietic precursors. In detail, several cell subsets, including stromal, endothelial cells, osteoblasts and immune cells, composing the peculiar leukemic niche, can actively interact with B-ALL blasts. Through deregulated molecular pathways they are able to influence leukemia development, survival, chemoresistance, migratory and invasive properties. The concept that the pre-leukemic and leukemic cell survival and evolution are strictly dependent both on genetic lesions and on the external signals coming from the microenvironment paves the way to a new idea of dual targeting therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

Dander

Palmi

D’Amico

et al. 2021

IJMS

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“…Elimination of M2 polarized macrophages from the tumor microenvironment with m909 could potentially improve the efficacy of chemotherapy or immunotherapy treatments targeting the tumor cells directly when used in combination. M2 polarized TAMs are also not unique to ovarian cancer and occur in the microenvironment of many solid cancers making their application broader [ 21 , 45 ]. Unfortunately, there are also challenges in replicating the tumor microenvironment and further experiments to demonstrate the efficacy of m909 in vivo or in combination with other therapeutic agents requires transitioning away from a human NK reconstituted mouse model, as a functional immune system is necessary to represent the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Folate Receptor Beta as a Direct and Indirect Target for Antibody-Based Cancer Immunotherapy

Roy

Robinson

Sharma

et al. 2021

IJMS

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Folate receptor beta (FRβ) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FRβ is commonly expressed at high levels on malignant blasts in patients with acute myeloid leukemia (AML), as well as on M2 polarized tumor-associated macrophages (TAMs) in the tumor microenvironment of many solid tumors. Therefore, FRβ is a potential target for both direct and indirect cancer therapy. We demonstrate that FRβ is expressed in both AML cell lines and patient-derived AML samples and that a high-affinity monoclonal antibody against FRβ (m909) has the ability to cause dose- and expression-dependent ADCC against these cells in vitro. Importantly, we find that administration of m909 has a significant impact on tumor growth in a humanized mouse model of AML. Surprisingly, m909 functions in vivo with and without the infusion of human NK cells as mediators of ADCC, suggesting potential involvement of mouse macrophages as effector cells. We also found that TAMs from primary ovarian ascites samples expressed appreciable levels of FRβ and that m909 has the ability to cause ADCC in these samples. These results indicate that the targeting of FRβ using m909 has the potential to limit the outgrowth of AML in vitro and in vivo. Additionally, m909 causes cytotoxicity to TAMs in the tumor microenvironment of ovarian cancer warranting further investigation of m909 and its derivatives as therapeutic agents in patients with FRβ-expressing cancers.

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“…In addition, Rodriguez-Garcia et al highlighted the role of folate receptor b (FRb) in TAMs cells. They demonstrated that immunosuppressive M2 TAMs expressing FRb promote tumor progression in a mouse model of ovarian cancer, pointing out FRb as a potential therapeutic target in combination with chemo-or immunotherapy (200). Furthermore, the expression of FRb in M2 TAMs correlated with a poor prognosis also in pancreatic cancer (201).…”

Section: Immune Cells Rewiring Therapiesmentioning

confidence: 99%

Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

et al. 2021

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Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME.

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CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy

Cited by 198 publications

References 102 publications

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

Folate Receptor Beta as a Direct and Indirect Target for Antibody-Based Cancer Immunotherapy

Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

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