The success of cancer immunotherapy relies on the knowledge of the tumor microenvironment and the immune evasion mechanisms in which the tumor, stroma, and infiltrating immune cells function in a complex network. The potential barriers that profoundly challenge the overall clinical outcome of promising therapies need to be fully identified and counteracted. Although cancer immunotherapy has increasingly been applied, we are far from understanding how to utilize different strategies in the best way and how to combine therapeutic options to optimize clinical benefit. This review intends to give a contemporary and detailed overview of the different roles of immune cells, exosomes, and molecules acting in the tumor microenvironment and how they relate to immune activation and escape. Further, current and novel immunotherapeutic options will be discussed.

/pdf/the-tumor-microenvironment-a-milieu-hindering-and-l0a6j22bpk.pdf

The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses

Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy.

Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.

Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.

Chronic low-grade inflammation is a common hallmark of the aging process and many age-related diseases. There is substantial evidence that persistent inflammation is associated with a compensatory anti-inflammatory response which prevents excessive tissue damage. Interestingly, the inflammatory state encountered with aging, called inflammaging, is associated with the anti-inflammaging process. The age-related activation of immunosuppressive network includes an increase in the numbers of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and macrophages (Mreg/M2c). Immunosuppressive cells secrete several anti-inflammatory cytokines, e.g., TGF-β and IL-10, as well as reactive oxygen and nitrogen species (ROS/RNS). Moreover, immunosuppressive cells suppress the function of effector immune cells by catabolizing L-arginine and tryptophan through the activation of arginase 1 (ARG1) and indoleamine 2,3-dioxygenase (IDO), respectively. Unfortunately, the immunosuppressive armament also induces harmful bystander effects in neighboring cells by impairing host tissue homeostasis. For instance, TGF-β signaling can trigger many age-related degenerative changes, e.g., cellular senescence, fibrosis, osteoporosis, muscle atrophy, and the degeneration of the extracellular matrix. In addition, changes in the levels of ROS, RNS, and the metabolites of the kynurenine pathway can impair tissue homeostasis. This review will examine in detail the harmful effects of the immunosuppressive cells on host tissues. It seems that this age-related immunosuppression prevents inflammatory damage but promotes the tissue degeneration associated with aging and age-related diseases. KEY MESSAGES: • Low-grade inflammation is associated with the aging process and age-related diseases. • Persistent inflammation activates compensatory immunosuppression with aging. • The numbers of immunosuppressive cells increase with aging and age-related diseases. • Immunosuppressive mechanisms evoke harmful bystander effects in host tissues. • Immunosuppression promotes tissue degeneration with aging and age-related diseases.

/pdf/increased-immunosuppression-impairs-tissue-homeostasis-with-4m1i4iid9m.pdf

Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases.

Interactions between tumor cells and tumor-associated macrophages (TAMs) are critical for glioblastoma progression. The TAMs represent up to 30% of the glioblastoma mass. The role of TAMs in tumor progression and in the mechanisms underlying tumor growth remain unclear. Using an in vitro model resembling the crosstalk between macrophages and glioblastoma cells, we show that glioblastoma-derived exosomes (GBex) reprogram M1 (mediate pro-inflammatory function) and M2 (mediate anti-inflammatory function) macrophages, converting M1 into TAMs and augmenting pro-tumor functions of M2 macrophages. In turn, these GBex-reprogrammed TAMs, produce exosomes decorated by immunosuppressive and tumor-growth promoting proteins. TAM-derived exosomes disseminate these proteins in the tumor microenvironment (TME) promoting tumor cell migration and proliferation. Mechanisms underlying the promotion of glioblastoma growth involved Arginase-1+ exosomes produced by the reprogrammed TAMs. A selective Arginase-1 inhibitor, nor-NOHA reversed growth-promoting effects of Arginase-1 carried by TAM-derived exosomes. The data suggest that GBex-reprogrammed Arginase-1+ TAMs emerge as a major source of exosomes promoting tumor growth and as a potential therapeutic target in glioblastoma.

https://www.mdpi.com/1422-0067/21/11/3990/pdf

Arginase-1+ Exosomes from Reprogrammed Macrophages Promote Glioblastoma Progression.

Metabolic pathways of L-arginine and therapeutic consequences in tumors

Sa1129: THERAPEUTIC EFFECT OF MITOCHONDRIA-TARGETING HYDROGEN SULFIDE PRODRUG, AP39 IN THE HEALING OF CHRONIC GASTRIC ULCERS

Hydrogen sulfide as a modulator of mitochondrial activity in the protection against oxidative NSAIDs-induced gastric injury

Tu1167b: INTRODUCTION TO THE THERAPEUTIC POTENTIAL OF CARBON MONOXIDE (CO) RELEASED FROM PHARMACOLOGICAL DONORS AGAINST BARRETT'S METAPLASIA AND ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPMENT

Aleksandra Danielak

Papers

Metabolic pathways of L-arginine and therapeutic consequences in tumors

Sa1129: THERAPEUTIC EFFECT OF MITOCHONDRIA-TARGETING HYDROGEN SULFIDE PRODRUG, AP39 IN THE HEALING OF CHRONIC GASTRIC ULCERS

Hydrogen sulfide as a modulator of mitochondrial activity in the protection against oxidative NSAIDs-induced gastric injury

Tu1167b: INTRODUCTION TO THE THERAPEUTIC POTENTIAL OF CARBON MONOXIDE (CO) RELEASED FROM PHARMACOLOGICAL DONORS AGAINST BARRETT'S METAPLASIA AND ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPMENT

Su1368 NOVEL APPROACH ON PEPTIC ULCER PHARMACOLOGY: THERAPEUTIC EFFECT OF MITOCHONDRIA-TARGETED HYDROGEN SULFIDE MOLECULES