Inhibition of adjuvant-induced TAM receptors potentiates cancer vaccine immunogenicity and therapeutic efficacy

Llópiz, Diana; Ruiz, Marta; Silva, Leyre; Repáraz, David; Aparicio, Belén; Egea, Josune; Lasarte, Juan José; Redín, Esther; Calvo, Alfonso; Angel, Matthew; Berzofsky, Jay A.; Stroncek, David F.; Sarobe, Pablo

doi:10.1016/j.canlet.2020.11.022

Cited by 7 publications

(12 citation statements)

References 52 publications

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“…In addition, AXL inhibitors have demonstrated efficacy alongside anti-tumor vaccines. In particular, TAM receptors were highly expressed in the monocyte-derived IL-10 + DC induced by the vaccine, and in a preclinical model, inclusion of an AXL inhibitor increased the immune response of the vaccine by regulating the expression of the TAM receptors ( 27 ). However, none of these previously published studies have described preclinical experiments that demonstrate the potential for improvement over the standard treatment methods currently applied in clinical practice, as well as a comprehensive analysis of the immune response.…”

Section: Discussionmentioning

confidence: 99%

“…No previous studies have shown a direct association between AXL and Tregs. It was known that TGF-β and epithelial-mesenchymal transition can promote the priming of induced Tregs in the tumor microenvironment ( 27 ). However, there is still no direct evidence regarding Treg regulation by AXL and further studies are needed to clarify this point.…”

Section: Discussionmentioning

confidence: 99%

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Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity

et al. 2022

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A recently developed treatment strategy for lung cancer that combines immune checkpoint inhibitors with chemotherapy has been applied as a standard treatment for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and it has improved the outcomes of chemotherapy. Maintenance treatment with anti-PD-1 antibody (aPD-1) enhances the effect of immunochemical combination therapy and improves therapeutic efficacy, which contributes toward a significant improvement in patient survival rates. The AXL receptor tyrosine kinase (AXL), which is expressed in tumor cells, plays an essential role in the resistance of cancers to chemotherapy and immunotherapy, and stimulates signaling associated with epithelial-mesenchymal transition (EMT) in metastatic cancer. AXL is thus an attractive target for controlling resistance to anti-tumor therapies. In this study, we examined the effect of AXL inhibitors on immune activation and tumor growth in TC1 and C3PQ mouse tumor models, in the context of clinical immunotherapy/chemotherapy and maintenance treatment, using an aPD-1 with/without pemetrexed. To determine the optimal timing for administration of SKI-G-801, an AXL inhibitor, we investigated its anti-tumor effects based on inclusion at the immunochemotherapy and maintenance therapy stages. We also performed flow cytometry-based immune profiling of myeloid cells and lymphoid cells at different points in the treatment schedule, to investigate the immune activation and anti-tumor effects of the AXL inhibitor. The addition of SKI-G-801 to the immune checkpoint inhibitor and chemotherapy stage, as well as the maintenance therapy stage, produced the best anti-tumor results, and significant tumor growth inhibition was observed in both the TC1 and C3PQ models. Both models also exhibited increased proportion of effector memory helper T cells and increased expression of CD86+ macrophages. Especially, regulatory T cells were significantly reduced in the TC1 tumor model and there was an increase in central memory cytotoxic T cell infiltration and an increased proportion of macrophages with high CD80 expression in the C3PQ tumor model. These results suggest increased infiltration of T cells, consistent with previous studies using AXL inhibitors. It is expected that the results from this study will serve as a stepping stone for clinical research to improve the existing standard of care.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity

et al. 2022

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“…IL-10 attenuates the activation of CD8 + T cells by reducing the production of IL-12 by DCs, thereby affecting the efficacy of chemotherapy. In a colon cancer model, a combination of a TAM inhibitor, IL-10 antagonist, and DC vaccine significantly increased CD8 + T-cell infiltration and optimized tumor shrinkage ( 63 , 64 ).…”

Section: Interaction Between Macrophages and The Tumor Immune Microen...mentioning

confidence: 99%

Role of macrophages in tumor progression and therapy (Review)

Wang

Liu

et al. 2022

Int J Oncol

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The number and phenotype of macrophages are closely related to tumor growth and prognosis. Macrophages are recruited to (and polarized at) the tumor site thereby promoting tumor growth, stimulating tumor angiogenesis, facilitating tumor cell migration, and creating a favorable environment for subsequent colonization by (and survival of) tumor cells. These phenomena contribute to the formation of an immunosuppressive tumor microenvironment (TME) and therefore speed up tumor cell proliferation and metastasis and reduce the efficacy of antitumor factors and therapies. The ability of macrophages to remodel the TME through interactions with other cells and corresponding changes in their number, activity, and phenotype during conventional therapies, as well as the association between these changes and drug resistance, make tumor-associated macrophages a new target for antitumor therapies. In this review, advantages and limitations of the existing antitumor strategies targeting macrophages in Traditional Chinese and Western medicine were analyzed, starting with the effect of macrophages on tumors and their interactions with other cells and then the role of macrophages in conventional treatments was explored. Possible directions of future developments in this field from an all-around multitarget standpoint were also examined.

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“…In recent years, chimeric antigen receptor (CAR) T cell therapy has developed rapidly in the treatment of hematological tumors. At the same time, human macrophages, which are modified with edited specific CAR to target antigen (such as CD19 and HER2) in order to recognize tumor cells and improve the ability of phagocytosis and antigen presentations, are in development as an immunotherapy [ 191 ]. The application of CAR-M therapy in solid tumors was first reported by Klichinsky et al in 2020 [ 192 ].…”

Section: Introductionmentioning

confidence: 99%

“…With the assistance of vaccine adjuvant cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs), the vaccine successfully increased the number of pro-inflammatory M1 macrophages, promoted the maturation of dendritic cells and activated memory T cells [ 194 ]. On the other hand, the combined vaccine which consists of therapeutic vaccine and TAMs receptor inhibitor provides a new way to treat cancer by inhibiting the up-regulated TAM receptors after vaccine treatment [ 191 ].…”

Section: Introductionmentioning

confidence: 99%

Dysregulated tumor-associated macrophages in carcinogenesis, progression and targeted therapy of gynecological and breast cancers

Zhang

et al. 2021

J Hematol Oncol

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Gynecological and breast cancers are a group of heterogeneous malignant tumors. Although existing treatment strategies have ameliorated the clinical outcomes of patients, the overall survival rate of advanced diseases remains unsatisfactory. Increasing evidence has indicated that the development and prognosis of tumors are closely related to the tumor microenvironment (TME), which restricts the immune response and provokes malignant progression. Tumor-associated macrophages (TAMs) are the main component of TME and act as a key regulator in tumor metastasis, immunosuppression and therapeutic resistance. Several preclinical trials have studied potential drugs that target TAMs to achieve potent anticancer therapy. This review focuses on the various functions of TAMs and how they influence the carcinogenesis of gynecological and breast cancers through regulating cancer cell proliferation, tumor angiogenesis and tumor-related immunosuppression. Besides, we also discuss the potential application of disabling TAMs signaling as a part of cancer therapeutic strategies, as well as CAR macrophages, TAMs-based vaccines and TAMs nanobiotechnology. These research advances support that targeting TAMs combined with conventional therapy might be used as effective therapeutics for gynecological and breast cancers in the future.

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Inhibition of adjuvant-induced TAM receptors potentiates cancer vaccine immunogenicity and therapeutic efficacy

Cited by 7 publications

References 52 publications

Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity

Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity

Role of macrophages in tumor progression and therapy (Review)

Dysregulated tumor-associated macrophages in carcinogenesis, progression and targeted therapy of gynecological and breast cancers

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