T cells against Solid Malignancies

Basics

    T lymphocytes activated in secondary lymphoid organs participate in anti-tumour immune response upon interaction with tumour-specific antigens. However, tumour cells develop an immune suppressive tumour micro-environment to escape and downregulate the immune system. T-cells are associated with the different immune responses against tumours, CD8+ cells and CD4 + cells (T memory cells) are pro-inflammatory and glutarate anti-tumour responses in Fas ligand, perforin/granzyme pathways (CD8+ cells) or CD8+ cell activation via T memory cells. Whereas, a subset of CD4+ cells, Tregs induce an anti-tumor immune response by inhibiting dendritic cell activation or producing anti-inflammatory cytokines. Dendritic cells present tumour cells to T cells and work in close aid to counter tumour growth for the infiltration of T lymphocytes in the TME, while NK cells kill tumour cells lacking the MHC complex, which is invisible to CD8+ cells. Anti-tumour immune cells are primitive glycolytic, while pro-tumour inducing immune cells are mainly oxidative and are in competition with tumour cells for glycolytic metabolism (NK cells, DC, T cells (CD8+, CD4+ Th 1, 17)) [7,8]. The γ/δ T-cells (a subset of T-cells), are marked with anti-tumor activity but with lower cell reactivity which favours T-cell transplant therapy. 

However, other tumor growth promoter (or immunosuppressive) immune cells such as ILC-2 or ILC-3 (innate lymphoid cells) reduces T-cell activity [7]. These subsets of T-Cells can also be part of immune-inflamed tumours, i.e. tumours have high penetration of immune cells and high concentration of pro-inflammatory cytokines in the tumour microenvironment. In solid malignancies, TME directly plays an important role in halting anti-tumour immune activity and promoting tumour growth. To overcome this problem, highly active anti-tumour chimeric T-cells should be developed with reduced cell reactivity. There are many pathways developed in tumour cells to reduce immune surveillance and promoting with a decreased display of MHC-I molecules (associated with tumours), and immune suppressive microenvironment (anti-inflammatory cytokines and immune suppressive cells). Increased expression of immune checkpoints (PDE-1 and CTLA-4) and altering metabolic homeostasis of immune cells [as both tumour and T-cells are glycolytic in nature with the faster glycolytic rate in tumour cells.

As discussed previously, PD-1 inhibits the PI3K/AKT/mTOR pathway in TLS to inhibit their proliferation and glycolytic metabolism. PGE2 and adenosine release by endothelial tumour cells kill T=cell growth in downregulating Fos1 expression. L-arginine is required for the memory T-cell [ CD4] proliferation and their survival, in which RNS (reactive nitrogen species) halt their growth, metabolic secretion, and TME matrix are the key things to be focused on in solid tumour for the targeted therapy. Immature vasculature in a chaotic manner inside solid tumors also halts the infiltration of T-cells. Regenerated lymphatic vessel transplants could provide new ways for T-cells (CTLs) to infiltrate and their long-lasting survival. TME in solid malignancies provides a holistic environment to T cells by releasing metabolic waste (lactic acid), low oxygen and nutrient supply, and low levels of cytosolic calcium required for cytokine secretion.

Receptors/islands/antigens/molecules/factors responsible for T-cell exhaustion or its senescence are IL-10, COX-2, TGF-B, NOS, PGE2, PDL-1, PDL-2, CTLA-4, Galactin 9, CTLA-4, GAL-3, TIM3, PD1, BTLA, TIGIT, excess cytosolic K+ ions, low cytosolic Ca+ ions. Various enzymes are involved in the regulation of T-cell metabolism and its anti-tumor activity. Activated CTLA4 increases the expression of protein phosphatase-2, a cell cycle regulator which further blocks the PI3/Akt/mTOR signalling axis and glucose uptake, thus reducing glycolytic metabolism in T cells. Inhibition of PIM kinase rebuilds the glucose metabolism and its anti-tumor function. Moreover, increased expression of mevalonate kinase (part of the MVK pathway) is correlated with the activation of T-cells. Increased IDO-1 expression and activated PPAR alpha-mediated high FAO in T-cells are generally marked with decreased anti-tumour T-cell responses. Thus, low OXPHOS and high glucose and glutamine metabolism are needed to support T-cell growth and activation for the anti-tumour response.

Points to be elaborated in future (Research Themes)

Rebuilding ECM for T-cell survival/ loosening the stiffness.

Regeneration of lymphatic vessels.

Reprogramming metabolic homeostasis.

Boosting T-cell timing and infiltration.

Analysing affinity and avidity of TCR during antigen presentation

Targeting tumour cells to display MHC complex.

Developing methods to redifferentiate exhausted T-cells to T-memory cells or T-cytotoxic cells

Depletion of suppressive immune cells in specific tumour site chemical modification (nitrosylation) of CCL-2 reduces the chemoattractant activity of CTLS but not MDSCs.   

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