Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance. 

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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

https://molecular-cancer.biomedcentral.com/counter/pdf/10.1186/s12943-021-01489-2

Abstract Emerging evidence indicates that the detection and clearance of cancer cells via phagocytosis induced by innate immune checkpoints play significant roles in tumor-mediated immune escape. The most well-described innate immune checkpoints are the “don’t eat me” signals, including the CD47/signal regulatory protein α axis (SIRPα), PD-1/PD-L1 axis, CD24/SIGLEC-10 axis, and MHC-I/LILRB1 axis. Molecules have been developed to block these pathways and enhance the phagocytic activity against tumors. Several clinical studies have investigated the safety and efficacy of CD47 blockades, either alone or in combination with existing therapy in hematological malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and lymphoma. However, only a minority of patients have significant responses to these treatments alone. Combining CD47 blockades with other treatment modalities are in clinical studies, with early results suggesting a synergistic therapeutic effect. Targeting macrophages with bispecific antibodies are being explored in blood cancer therapy. Furthermore, reprogramming of pro-tumor macrophages to anti-tumor macrophages, and CAR macrophages (CAR-M) demonstrate anti-tumor activities. In this review, we elucidated distinct types of macrophage-targeted strategies in hematological malignancies, from preclinical experiments to clinical trials, and outlined potential therapeutic approaches being developed. 

/pdf/targeting-macrophages-in-hematological-malignancies-recent-1smcatcl.pdf

Targeting macrophages in hematological malignancies: recent advances and future directions

Hypersialylation is a common post-translational modification of protein and lipids found on cancer cell surfaces, which participate in cell-cell interactions and in the regulation of immune responses. Sialic acids are a family of nine-carbon α-keto acids found at the outermost ends of glycans attached to cell surfaces. Given their locations on cell surfaces, tumor cells aberrantly overexpress sialic acids, which are recognized by Siglec receptors found on immune cells to mediate broad immunomodulatory signaling. Enhanced sialylation exposed on cancer cell surfaces is exemplified as “self-associated molecular pattern” (SAMP), which tricks Siglec receptors found on leukocytes to greatly down-regulate immune responsiveness, leading to tumor growth. In this review, we focused on all 15 human Siglecs (including Siglec XII), many of which still remain understudied. We also highlighted strategies that disrupt the course of Siglec-sialic acid interactions, such as antibody-based therapies and sialic acid mimetics leading to tumor cell depletion. Herein, we introduced the central roles of Siglecs in mediating pro-tumor immunity and discussed strategies that target these receptors, which could benefit improved cancer immunotherapy.

Siglecs as Therapeutic Targets in Cancer.

Sialic acid-binding receptors are expressed on the surfaces of a variety of immune cells and have complex and diverse immunoregulatory functions in health and diseases. Recent studies have shown that Siglecs could play diverse immune and nonimmune regulatory roles in the tumor microenvironment (TME) and participate in tumor progression through various mechanisms, such as regulating tumor growth and metastasis, mediating the inflammatory response, and promoting tumor immune escape, thereby affecting the prognoses and outcomes of patients. However, depending on the cell type in which they are expressed, each Siglec member binds to corresponding ligands in the microenvironment milieu to drive diverse cell physiological and pathological processes in tumors. Therefore, we herein summarize the expression spectra and functions of the Siglec family in human diseases, particularly cancer, and highlight the possibility of therapeutic interventions targeting the TME in the future. 

/pdf/the-intriguing-roles-of-siglec-family-members-in-the-tumor-2tzvzi9t.pdf

The intriguing roles of Siglec family members in the tumor microenvironment

Tumor-associated macrophages (TAMs) promote key processes in the modulation of tumor microenvironment (TME). However, the clinical significance of heterogeneous subpopulations of TAMs in hepatocellular carcinoma (HCC) remains unknown. HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas were obtained and analyzed. Immunohistochemistry and flow cytometry were performed to detect the characteristics of sialic acid-binding immunoglobulin-like lectin 10high (Siglec-10hi) TAMs and explore their impact on the TME of HCC. The effect of Siglec-10 blockade was evaluated in vitro based on fresh human tumor tissues. Our data revealed that Siglec-10 was abundant in a large proportion of HCC specimens and prominently distributed on macrophages. Kaplan–Meier curves and Cox regression analysis showed that intratumoral Siglec-10+ cell enrichment was associated with unfavorable prognosis in patients with HCC. Notably, multiple anti-inflammatory cytokines and inhibitory receptors were enriched in Siglec-10hi TAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10hi TAMs. High infiltration of Siglec-10hi TAMs was associated with impaired CD8+ T cell function in HCC. Of note, blocking Siglec-10 with the competitive binding antibody Siglec-10 Fc led to decreased expression of immunosuppressive molecules and increased the cytotoxic effects of CD8+ T cells against HCC cells. Moreover, blocking Siglec-10 promoted the anti-tumor efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab. Siglec-10hi TAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10hi TAMs may serve as a promising immunotherapy approach for HCC.

/pdf/blocking-siglec-10hi-tumor-associated-macrophages-improves-2s9bu64ung.pdf

Blocking siglec-10hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma.

CD74 was initially thought to participate mainly in antigen presentation as an MHC class II chaperone. Recent studies have shown that CD74 plays an important role within the cell and throughout the immune system in a wide spectrum of neoplasms. However, the role of CD74 in hepatocellular carcinoma (HCC) remains elusive. In this study, HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas (TCGA) were obtained and analyzed. Immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq) were performed to detect the characteristics of CD74+ cells and explore their impact on the tumor microenvironment (TME) of HCC. Our data revealed that stromal CD74+ cell enrichment was associated with favorable prognosis in patients with HCC. CD74 was abundant in a large portion of HCC specimens and prominently distributed on stromal macrophages. scRNA-seq data also indicated that the pathways related to immune response were significantly upregulated in CD74+ macrophages. High infiltration of CD74+ macrophages was associated with increased infiltration of CD8+ cytotoxic T lymphocytes (CTLs) with enhanced effector functions in HCC. Besides, blocking CD74 weakened the antitumor activity and proliferation ability of CD8+ CTLs in HCC. Our findings highlight the critical role of CD74 in HCC. New drugs and antibodies targeting CD74 may be effective strategies for HCC therapy.

Kangshuai Li

Papers

Blocking siglec-10hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma.

CD74+ macrophages are associated with favorable prognosis and immune contexture in hepatocellular carcinoma