Notes

Growth Microenvironment Modulating Functional Nanoparticles for Effective Cancer Treatments.
Colorectal cancer (CRC) represents a major public health challenges, with one of the highest incidences worldwide. The two affected anatomical sites in CRC, i.e. the colon and the rectum, share important underlying features, but often differ in terms of therapeutic management. Current guidelines for CRC define its clinical stratification according to classical, tumor cell-based and pathological parameters. Novel ground-breaking findings in the recent years revealed the prominent role of the immune system in shaping CRC development. This chapter provides a detailed overview of the main genomic and immune features driving (or hampering) CRC progression, with a focus on the main immune cells and factors shaping its evolution. Furthermore, we discuss how tumor-infiltrating immunity could be leveraged both for therapeutic and stratification purposes.Checkpoint inhibitor therapy (CIT) has revolutionized cancer treatment but it has also reached a standstill when an absent dialog between cancer and immune cells makes it irrelevant. This occurs with high prevalence in the context of "immune silent" and, even perhaps, "immune-excluded" tumors. The latter are characterized by T cells restricted to the periphery of cancer nests. Since in either case T cells do not come in direct contact with most cancer cells, CIT rests immaterial. Adoptive cell therapy (ACT), may also be affected by limited access to antigen-bearing cancer cells. While lack of immunogenicity intuitively explains the immune silent phenotype, immune exclusion is perplexing. The presence of T cells at the periphery suggests that chemo-attraction recruits them and an immunogenic stimulus promotes their persistence. However, what stops the T cells from infiltrating the tumors' nests and reaching the germinal center (GC)? Possibly, a concentric gradient of increased chemo-repulsion or decreased chemnce the effectiveness of immune oncology (IO) approaches.The development of cancer results from the evolutionary balance between the proliferating aptitude of cancer cells and the response of the host's tissues. Some cancers are characterized by genetic instability dependent upon impaired DNA repair mechanisms that lead to the chaotic disruption of multiple cellular functions often in excess of the cancer survival needs and may exert broad effects on surrounding tissues, some beneficial and some detrimental to cancer growth. Among them, inflammatory processes that accompany wound healing may initiate a reaction of the host against the neo-formation. This is possibly triggered by the release by dying cancer cells of molecules known as Damage-Associated Molecular Patterns (DAMPs) following a process termed Immunogenic Cell Death (ICD) that initiates an immune response through innate and adaptive mechanisms. Indeed, analysis of large cancer data sets has shown that ICD is strictly associated with the activation of other immune effector or immune-regulatory pathways. Here, we will describe how immune activation and compensatory immune-regulatory mechanisms balance anti-cancer immune surveillance and the roles that innate and adaptive immunity play including the weight that neo-epitopes may exert as initiators and sculptors of high-affinity memory and effector immune responses against cancer. We will discuss the evolutionary basis for the existence of immune checkpoints and how several theories raised to explain cancer resistance to immunotherapy represent a facet of a similar evolutionary phenomenon that we described in the Theory of Everything. We will show how the biology of immunogenicity and counterbalancing immune regulation is widespread across cancers independent of their ontogenesis while subtle idiosyncratic differences are discernible among them. Finally, we will suggest that overcoming immune resistance implies distinct approaches relevant to the immune context of individual cancers.The adaptive immune response is a 500-million-year-old (the "Big Bang" of Immunology) collective set of rearranged and/or selected receptors capable of recognizing soluble and cell surface molecules or shape (B cells, antibody), endogenous and extracellular peptides presented by Major Histocompatibility (MHC) molecules including Class I and Class II (conventional αβ T cells), lipid in the context of MHC-like molecules of the CD1 family (NKT cells), metabolites and B7 family molecules/butyrophilins with stress factors (γδT cells), and stress ligands and absence of MHC molecules (natural killer, NK cells). What makes tumor immunogenic is the recruitment of initially innate immune cells to sites of stress or tissue damage with release of Damage-Associated Molecular Pattern (DAMP) molecules. Subsequent maintenance of a chronic inflammatory state, representing a balance between mature, normalized blood vessels, innate and adaptive immune cells and the tumor provides a complex tumor microenvironment serving as the backdrop for Darwinian selection, tumor elimination, tumor equilibrium, and ultimately tumor escape. Effective immunotherapies are still limited, given the complexities of this highly evolved and selected tumor microenvironment. Cytokine therapies and Immune Checkpoint Blockade (ICB) enable immune effector function and are largely dependent on the shape and size of the B and T cell repertoires (the "adaptome"), now accessible by Next-Generation Sequencing (NGS) and dimer-avoidance multiplexed PCR. MLN8237 purchase How immune effectors access the tumor (infiltrated, immune sequestered, and immune desserts), egress and are organized within the tumor are of contemporary interest and substantial investigation.It is increasingly recognized that cancer does not involve only formation of a tumor, but also systemic changes in the host. Alterations in number, spatial relationship, and function of immune cells have been identified in cancer patients' blood, lymph nodes, spleen, and bone marrow. Importantly, these changes correlate with clinical outcome, demonstrating that systemic effects may persist in some patients after initial therapy that underlie future relapse. In this chapter, we will review these recent findings on the systemic effects of cancer.
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