Cancer Cachexia and Antitumor Immunity: Common Mediators and Potential Targets for New Therapies

Abstract

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host's innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host's metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals.

Keywords: PD-1; antitumor immunity; cachexia pathogenesis; cancer cachexia; cytokines; immune checkpoint inhibitors; immunotherapy; resistance to immunotherapy; tumor microenvironment.

Figure 1

The complexity of effects induced by a plethora of cachexia mediators leading to immune suppression and alteration in muscle and adipose tissue composition. Abbreviations: ActRIIB: Τype IIβ Activin receptor, CAF: Cancer associated fibroblast, CXCR1/2: C-X-C motif chemokine receptor 1–2, DC: Dendritic cell, EMT: Epithelial-to-mesenchymal transition, gp130: Glycoprotein 130, MDSC: Myeloid derived suppressor cell, M1 and M2: M1 and M2 macrophage subtypes, N1 and N2: N1 and N2 tumor infiltrating neutrophils subtypes, NK: Natural killer cell, NLP3: Nodule inception protein-like protein 3, PPARα: Peroxisome proliferator-activated receptor alpha, TGFβR1-3: Transforming growth factor beta receptors 1–3, TIM3: T-cell immunoglobulin and mucin-domain containing-3, TNFR1: Tumor necrosis factor receptor 1.

Figure 2

(A) P-selectin-PSGL-1 interaction enables the infiltration of the MDSCs in the TME which suppress the antitumor effects of T-cells. (B) Inhibition of P-selectin/PSGL-1 interaction can block MDSC cell recruitment in the TME and increase the accumulation of intratumoral effector T cells, thus potentiating the effect of anti-PD-1 treatment. Abbreviations: MDSC: Myeloid derived suppressor cell, PSGL-1: P-selectin glycoprotein ligand 1.