Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Immune analysis of on-treatment longitudinal biopsies predicts response to melanoma immunotherapy


MD Anderson News Release 08/10/2016

Immune response measured in tumor biopsies during the course of early treatment predicts which melanoma patients will benefit from specific immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center report in the journal Cancer Discovery.


Gene profiling identifies resistance mechanisms

As with the immune profiling, the gene expression panel turned up significant differences between responders and non-responders only at the on-treatment biopsy for anti-PD1. Significant differences were found in 411 differentially expressed genes in responders.

Most differences involved increased expression in the responding patients of genes involved in immune response. Only six genes were lower in responders, including the vascular endothelial growth factor (VEGFA), which is involved in the generation of new blood vessels, or angiogenesis.

This suggests a targetable mechanism for resistance to treatment, Wargo said, which is consistent with findings by others. Anti-PD1 therapy is being tested with VEGF inhibitors in clinical trials now.

Potential mechanisms of therapeutic resistance to PD-1 based therapy were also identified through defects in interferon signaling and altered antigen processing and presentation – essentially allowing tumors to “hide” from killer T cells. Another paper will more fully report genomic results.



https://www.mdanderson.org/newsroom/201 ... -of-o.html

Impaired interferon signaling is a common immune defect in human cancer


Abstract

Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-α)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-γ)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.

Immune dysfunction is an early event in cancer development and expands with progression to metastatic disease (1). Tumor-associated antigen (TAA)-specific CD8 T lymphocytes are often present in the blood of cancer patients and accumulate at tumor sites and in tumor-draining lymph nodes (2). While TAA-specific CD8 T cells can be elicited by current peptide vaccines and other immunotherapies, the presence or magnitude of these responses does not reliably correlate with clinical outcome or response to vaccination (3–5). Such cells may be specifically driven into apoptosis or rendered nonresponsive in vivo, preventing appropriate activation and cytolytic responses against tumor cells (6, 7). Current immunotherapeutic strategies are subject to the immunosuppressive effects of cancer and of regulatory T cells, which likely contribute to their lack of success thus far (4, 5). The nature and molecular mechanisms underlying immune dysfunction in cancer are not clearly defined. Elucidation of the mechanisms will allow rational design of strategies to reverse immune dysfunction and normalize lymphocyte populations to improve the endogenous immune response to cancer and to enhance the efficacy of cancer immunotherapy.

*Potential mechanisms of immune dysfunction in cancer include defects in antigen recognition (first signal), costimulation (second signal), and cytokines, (e.g., IFNs; third signal). Efficient IFN signaling is critical to provide the third signal to enable full activation, clonal expansion, and memory development rather than tolerance (8), and for efficient natural killer (NK)-cell-mediated cytotoxicity (9). We hypothesized that impaired IFN signaling may be a common immune defect in cancer patients (10). This study aimed to determine whether altered IFN signaling is a general mechanism of immune function in patients with cancer of different types and stages. A further aim of this study was to assess which subsets of peripheral blood leukocytes exhibit defects in IFN signaling, and which downstream IFN-stimulated functional responses are affected. We assessed IFN signaling in peripheral blood lymphocytes from patients with 3 major types of cancer via real-time quantitative PCR to measure expression of IFN-stimulated genes (ISGs), extensive Phosflow analyses, and functional analyses to measure downstream responses to IFNs. STAT1 tyrosine-701-phosphorylation (pSTAT1) is critical for both type-I and -II IFN signaling via the JAK-STAT pathway (11); therefore, we assessed pSTAT1 in response to IFN-α or -γ in T, B, and NK cells from cohorts of breast cancer patients, melanoma patients, gastrointestinal (GI) cancer patients (including colon, rectum, stomach, and pancreatic cancer), and compared against age-matched healthy controls. Our analyses included the main peripheral blood lymphocyte populations that are involved in tumor immunity and may be negatively impacted or promoted by tumors, specifically T cells, including naive, effector and memory subsets, B cells, and NK cells. IFN signaling is critical in the proper activation and homeostatic control of these cell types, and impaired IFN signaling in these cell types may aid tumor progression and confound immunotherapeutic approaches.



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Results
ISG Expression Is Down-Regulated in Lymphocytes from Breast Cancer Patients. To assess the integrity of the IFN-signaling pathway in lymphocytes




http://www.pnas.org/content/106/22/9010.full

*Potential mechanisms of immune dysfunction in cancer include defects in antigen recognition (first signal), costimulation (second signal), and cytokines, (e.g., IFNs; third signal

)

Each antibody is specifically produced by the immune system to match an antigen after cells in the immune system come into contact with it; this allows a precise identification of the antigen and the initiation of a tailored response.
https://en.wikipedia.org/wiki/Antigen

Co-stimulation
During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors

https://en.wikipedia.org/wiki/Co-stimulation

Cytokine
Cytokines are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. They are released by cells and affect the behavior of other cells. Cytokines can also be involved in autocrine signaling

a cool utube teaching

https://www.youtube.com/watch?v=vx0yL3owNmU

definition
http://en.wikipedia.org/wiki/Cytokine

The article

Chapter 3Antigen Recognition by B-cell and T-cell Receptors

"We have learned in Chapter 2 that the body is defended by innate immune responses, but these will only work to control pathogens that have certain molecular patterns or that induce interferons and other secreted yet non-specific defenses. Most crucially, they do not allow memory to form as they operate by receptors that are coded in the genome. Thus, innate immunity is good for preventing pathogens from growing freely in the body, but it does not lead to the most important feature of adaptive immunity, which is long-lasting memory of specific pathogen.

To recognize and fight the wide range of pathogens an individual will encounter, the lymphocytes of the adaptive immune system have evolved to recognize a great variety of different antigens from bacteria, viruses, and other disease-causing organisms. The antigen-recognition molecules of B cells are the immunoglobulins, or Ig. These proteins are produced by B cells in a vast range of antigen specificities, each B cell producing immunoglobulin of a single specificity (see Sections 1-8 to 1-10). Membrane-bound immunoglobulin on the B-cell surface serves as the cell's receptor for antigen, and is known as the B-cell receptor (BCR). Immunoglobulin of the same antigen specificity is secreted as antibody by terminally differentiated B cells—the plasma cells. The secretion of antibodies, which bind pathogens or their toxic products in the extracellular spaces of the body, is the main effector function of B cells in adaptive immunity.

Antibodies were the first molecules involved in specific immune recognition to be characterized and are still the best understood. The antibody molecule has two separate functions: one is to bind specifically to molecules from the pathogen that elicited the immune response; the other is to recruit other cells and molecules to destroy the pathogen once the antibody is bound to it. For example, binding by antibody neutralizes viruses and marks pathogens for destruction by phagocytes and complement, as described in Section 1-14. These functions are structurally separated in the antibody molecule, one part of which specifically recognizes and binds to the pathogen or antigen whereas the other engages different effector mechanisms. The antigen-binding region varies extensively between antibody molecules and is thus known as the variable region or V region. The variability of antibody molecules allows each antibody to bind a different specific antigen, and the total repertoire of antibodies made by a single individual is large enough to ensure that virtually any structure can be recognized. The region of the antibody molecule that engages the effector functions of the immune system does not vary in the same way and is thus known as the constant region or C region. It comes in five main forms, which are each specialized for activating different effector mechanisms. The membrane-bound B-cell receptor does not have these effector functions, as the C region remains inserted in the membrane of the B cell. Its function is as a receptor that recognizes and binds antigen by the V regions exposed on the surface of the cell, thus transmitting a signal that causes B-cell activation leading to clonal expansion and specific antibody production.

The antigen-recognition molecules of T cells are made solely as membrane-bound proteins and only function to signal T cells for activation. These T-cell receptors (TCRs) are related to immunoglobulins both in their protein structure—having both V and C regions—and in the genetic mechanism that produces their great variability (see Section 1-10 and Chapter 4). However, the T-cell receptor differs from the B-cell receptor in an important way: it does not recognize and bind antigen directly, but instead recognizes short peptide fragments of pathogen protein antigens, which are bound to MHC molecules on the surfaces of other cells.

The MHC molecules are glycoproteins encoded in the large cluster of genes known as the major histocompatibility complex (MHC) (see Sections 1-16 and 1-17). Their most striking structural feature is a cleft running across their outermost surface, in which a variety of peptides can be bound. As we shall discuss further in Chapter 5, MHC molecules show great genetic variation in the population, and each individual carries up to 12 of the possible variants, which increases the range of pathogen-derived peptides that can be bound. T-cell receptors recognize features both of the peptide antigen and of the MHC molecule to which it is bound. This introduces an extra dimension to antigen recognition by T cells, known as MHC restriction, because any given T-cell receptor is specific not simply for a foreign peptide antigen, but for a unique combination of a peptide and a particular MHC molecule. The ability of T-cell receptors to recognize MHC molecules, and their selection during T-cell development for the ability to recognize the particular MHC molecules expressed by an individual, are topics we shall return to in Chapters 5 and 7.

In this chapter we focus on the structure and antigen-binding properties of immunoglobulins and T-cell receptors. Although B cells and T cells recognize foreign molecules in two distinct fashions, the receptor molecules they use for this task are very similar in structure. We will see how this basic structure can accommodate great variability in antigen specificity, and how it enables immunoglobulins and T-cell receptors to carry out their functions as the antigen-recognition molecules of the adaptive immune response."


https://www.ncbi.nlm.nih.gov/books/NBK10770/