Immunoediting: The Cancer Landscape

2019 John A. Catanzaro

Please go to LinkedIn: https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

Image for post
Image for post

Introduction

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. In this review, I am going to discuss the key features and observation of cancer cells, tumor microenvironment and immunoediting mechanisms.

Immunoediting

Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

It all begins with the damaged single cell. When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point its either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system.

Chop Molecular and Immune Suey

Chop Suey (雜碎) in Chinese means, “mixed bits.” Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells. A moiety of normal and a moiety of mess. The challenge is scavenge the mess and amplify the normal. Easier said than done, but totally doable!

Image for post
Image for post

In this mixed moiety it’s like being in a room with many people, if a person is tone deaf it all sounds like a cacophony of noise. A harsh mixture of sounds that are discordant and cannot be deciphered with ease. Cancer, multi-disease, or any disease, is simply that harsh mixture of discordant exposure and mechanisms that adversely effect the symbiotic balance of the whole.

Image for post
Image for post

A tumor just doesn’t become a tumor by chance it becomes a tumor by intentional evolution. It’s just as intentional as an embryo growing (fetus) in the uterus, but without the unified hierarchy of specialized cell order and control that architects the life of a new human being! It is an intentional chaotic mess of mixed up messages with a distinct order that has to overcome overwhelming odds to survive. A tumor then becomes “mixed bits,” of everything including elements of the immune system that create an immune landscape that is contrary to the detection and defense attack of the tumor. Simply called resistance, evasion or escape causing invasion, proliferation and colonization in areas away from the primary tumor. The interesting aspect here, when this escape occurs the progeny of cells can transform into a higher grade mutation unlike the original cancer cells / tumor cells that constructed the original tumor. https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

Cancer Biology Overcoming Overwhelming Odds For Survival

The good news is that the survival rate and overcoming the odds of this multi-disease is on the rise. However, the number of new cancers developing is also on the rise. What does the cancer biology do to increase chances of survival and minimize immune surveillance and defense? Simply, it continues in the affinity of the environment that initiated its action and the continuous adaptation to evade the forces that will induce its destruction. Assess the environment that initiated the molecular chaos and amplify immune defense and regulation mechanisms featured in the immunoediting architecture. Cancer Stats 2018

When cancer cells and tumor cells escape and enter the blood circulation, the hydrodynamic and physical shear forces in the circulation can tear cancer cells and escaping tumor cells apart. Experimental studies of metastasizing cancer cells in the general circulation is greatly enhanced if they can attract an entourage of blood platelets and other inflammatory mediated immune cells to escort them through the rapids into safe pools within tissues. Clearing away the cancer clutter and identify viable targets within this cluttered schema is of critical importance.

Circulating Cancer Cells and Circulating Tumor Cell Clusters

Image for post
Image for post

In the cancer biology molecular schema, circulating cancer cells (CTC) have characteristically deranged DNA. The molecular characterization of CTC and CTC clusters will revolutionize our interpretation of cancer metastasis. Cancer hallmark biological analytics and immunocentrics is a platform that unifies cancer life cycle pathways and HLA compatibility affinities. This includes CTC differentiation and immunoediting relationships. The construct of CTC clusters is made up of a sticky adhesive inflammation group of cells which include platelets, inflammatory cytokines, stromal cells, sheared damaged RBC’s, exosomes and other related anti-inflammatory and inflammatory based immune cells. Resistance of programmed cell death, margination, adhesion, interception and matrix degradation are all characteristics of metastasis formation that are all observed features of the CTC clusters. https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

Image for post
Image for post

Clarification On Tumor Associated Macrophages (TAM’s M1 and M2)

Macrophages are part of innate immune defenses. They displays a differential expression profile of cytokines, enzymes, and cell-surface markers and are derived from monocytes. Macrophages have been divided into two subtypes: M1 and the alternative M2 macrophages.

The M1 phenotype is driven by Th1 cytokine interferon-γ, bacterial moieties such as lipopolysaccharide (LPS), and Toll-like receptor (TLR) agonists. They are characterized by the production of pro-inflammatory cytokines such as IL-6, IL-12, IL-23, and tumor necrosis factor-α (TNF-α).

The M1 macrophages express high levels of the major histocompatibility complex class I and class II molecules that are required for the presentation of tumor-specific antigens. The M1 macrophages serve as a critical cellular component involved in the inflammatory response and anti-tumor immunity.

Conversely, the M2 macrophages exert anti-inflammatory and pro-tumorigenic activities. The M2 macrophages can be further subdivided into subsets called M2a, M2b, M2c, and M2d. The Th2 cytokines such as IL-4 and IL-13 can stimulate the conversion of macrophage to M2a phenotype, whereas the activation of TLRs and immune complexes induces the M2b macrophages, and IL-10 polarizes the M2c subtype.

Image for post
Image for post

Within the tumor, macrophages are a major stromal component, where they are commonly termed TAMs. TAMs exhibit functions similar to those of M2 macrophages and can be characterized as the M2d subtype. During tumor development, tumor-infiltrating M1-polarized macrophages are generally characterized by an IL-12high IL-10low phenotype and promote immune responses that elicit tumor cell disruption.

During late-stage tumor progression, TAMs generally switch to an M2-like phenotype characterized by an IL-12low IL-10high phenotype and low tumoricidal activity. Such TAMs have been shown to provide a favorable microenvironment for tumor growth, tumor survival, and angiogenesis.

Image for post
Image for post

Chemotherapeutic resistance occurs resulting from cancer stem cells (CSC) self-renewal progeny that have varying degrees of expression within each new developing progeny. Therefore, it becomes essential for a TAM-Targeting approach to amplify immunoediting cascade favoring tumor regression. In personalized cancer vaccine therapeutics these considerations are possible through Cancer Hallmark and HLA Affinity profiling of the patient.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

Clarification on Myeloid Derived Suppressor Cells (MDSC’s)

Image for post
Image for post
Image for post
Image for post

Myeloid-Derived Suppressor Cells (MDSC’s) cause tumor microenvironment resistance and are immunosuppressive. Tumor and immune cells constantly release inflammatory mediators leading to dysregulation of production of myeloid cells and the conversion of immature myeloid cells in the bone marrow. MDSC’s are targetable in the personalized therapeutic applications landscape and should be considered if Cancer Hallmark Analytic and Immunocentric mapping and selection affinity give clear distinction as to the role confidence MDSC’s play in tumor resistance. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

Adipocytes and Adipose Tissue In Tumor Progression and Chemo Resistance

Image for post
Image for post

Growing evidence raised the important roles of adipocytes as an active player in the tumor microenvironment. In many tumors adipocytes are in close contact with cancer cells. They secrete various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. In addition, patterns of chemotherapeutic resistance is observed in several cancer types including melanoma breast cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

Clearing the Cancer Clutter (Cancer Immune Cycle)

Image for post
Image for post

Favorable Constituents to Initiate Immunity:

  • Dendritic Cells
  • T Cell Trafficking
  • Immune mediating cytokines (Th1) chemokines favorable in anti-tumor defense
  • M1 Macrophages
  • Cancer cell and tumor related antigens (TAA and TSA)
  • Fragmented cancer related DNA
  • NK-mediated tumor lysis

The presentation of these elements will initiate immune responses against cancer cells and tumor cells in circulation and in the tumor microenvironment. The current complexity is predicting the efficiency of cascade immunity in cancer and intervening in the faults created by the cancer life cycle that interfere or evade immune features required in cancer defense. https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

Image for post
Image for post

Unfavorable Constituents in Immune Resistance

Image for post
Image for post
  • Immunosuppressive regulatory T cells
  • Protumoral mast cells
  • Cancer-associated fibroblasts (CAF’s)
  • Myeloid derived suppressor cells (MDSC’s)
  • Tissue resident fibroblasts
  • Immune mediating cytokines (Th2) and chemokines unfavorable in initiating tumor resistance
  • Tumor-associated macrophages (TAM’s) M2 Macrophages
  • Dysfunctional adipocytes
  • Tumor cells resistant to NK-mediated lysis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

Image for post
Image for post

Achieving Immunoediting In Favor Of Cancer Regression

Image for post
Image for post
Image for post
Image for post

Immunoediting is a primary push-button feature that we definitely want to hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As I mentioned above the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. However, the antithesis is the tumor microenvironment creating its own immunity causing resistance and detection avoidance (immunosurveillance) from outside its own environment. It is essential to visualize the intrinsic mechanisms of tumor defense and regression based upon the elimination, equilibrium and escape model. The three components are represented respectively as anti-tumor defense (tumor immunity), tumor dormancy and tumor progression. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

Dendritic Neoantigens and Transcriptome Payloads In Personalized Treatment

Image for post
Image for post
Image for post
Image for post
Image for post
Image for post

Personalized (Precision-Based) cancer vaccines must become the primary form of treatment. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. We are commonly observing resistance to chemotherapeutic and biologics. We observe the tumor microenvironment tolerance of these agents with increased risk of more complicated molecular and immunoediting mechanisms and expression seen in favor of cancer survival than is observed in cancer regression. These personalized treatments will be developed in concert with Cancer Hallmark Analytics and Immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

Cancer Hallmark Pathway Studio and HLA Affinity Immunocentrics

Image for post
Image for post

The Cancer Hallmark Pathway Studio and HLA Affinity Immunocentrics has patientcentricity at the core of its platform. Molecular and immunoediting feature integration provides affinity pathway mapping and selection mapping to derive the therapeutic “best fit” for the patient. Any personalized treatment payload can be plugged into this integration. This platform is an expandable model and is useful in identifying the best targets in molecular and immunoediting pathways throughout the life cycle of the cancer. This is vitally important in creating a re-edit of any therapeutic application to address the cancer resistance. The patient can be profiled at intervals to determine any changes in pathway and affinity expression. You may go to this link to learn more on the Cancer Hallmark Analytics and Immunocentrics Platform. https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

Summary

Image for post
Image for post

I have outlined some very essential elements involved in cancer biology and immune defense. I tried to compact this in order to create an inspirational model of what can be achieved in profiling and delivery of patient personalized therapeutic applications. As research continues all of these elements will expand and revise, The beauty of this model is that it expands and adapts. The cancer molecular biological evolution continues to expand and adapt. All the more reason to be ahead of the molecular and immunoediting mechanisms in involved. Staying ahead of mutation, migration and proliferation is the key to an expandable personalized treatment model.

John A. Catanzaro is CEO of Neo7logix, a bioscience company that designs precision and personalized treatment designs. www.neo7logix.com

Get the Medium app

A button that says 'Download on the App Store', and if clicked it will lead you to the iOS App store
A button that says 'Get it on, Google Play', and if clicked it will lead you to the Google Play store