Cancer Immunology

Oncogenes

Drive abnormal cell proliferation via genetic increased gene expression or uncontrolled oncogene activity

Tumor Suppressor genes

Inhibit cell proliferation and tumor development. lost or inactive in tumors

What happens when you remove tumor suppresor genes

TUMORS DUH - abnormal proliferation of cells

what is the Two-hit hypothesis

most tumor suppressor genes require both alleles to be inactivated

Physiological Myc

Transcriptional control - cells thrive in a controlled cell cycle

Degregulated MYC

Collapsed control under an abnormal cell cycle leading to tumorgenesis

6 hallmarks of cancer

• Evadiing apoptosis

• Self-sufficient growth signals

• insensitivtey to anti-growth signals

• Tissue invasion

• limitless proliferation

• sustained angiogenesis

are tumors just cancer cells

NO! fibroblasts, cancer cells, endothelial cells, immune cells, pericytes

once the tumor binds to the endothelial cells what happens

tumor gets a blood supply → grows → tumors travel through tissues

Cold tumor

• Exclusion of CD8+ and NK

• Tregs in Tumor

• Poor prognosis and therapy response

Hot tumor

• CD8 and Nk cells in tumor

• no immunosuppressive cell types

• Better prognosis and therapy reaction

what kind of cells are tumors

self cells - contain self proteins

how do tumors happen

Integrated stress response - incrorrect folding and transcription

Subverts nutrients - immune cells cant respond and recognize w/out nutrients

Recognition fo stressed induced ligrands - cellular stress

Reducing the MHC 1 - t cells cant recognize tumor

How to find a tumor without MHC1

Nk cells

TME

tumor Microenvironment

Immune activation in the TME

Nk cells, DAMPS, PAMPS, Stres repsponse

Integrated stress response

Signalling network - activates eIF2 leading to ATF4 activation = regulatory protein in order to return to homeostasis

Immune inhibition on the TME

Transformign growth factor beta (inhibatory cytokine) to inhibit immune cell funtion

CYclo-oxygenase 2 - inflammatory mediators

M1 macrophages

• Proinflam

• antitumoral

• Tissue-specific antigen presentation

• tissue injury

what causes M1 macrophages

Th1 respinse - IFNy and TNFa

What causes M2 macrophages

TH2 - IL-4/10/13

M2 macrophages

• Antiinflam.

• Pro-tumoral

• wound healing

• parasite clearance

• immunosuppression

TIL

Tumor infiltrating lymphocytes - marker of a good prognosis

immunotherapy in cancer

inhibiting immune checkpoints with antibodies

t-cell targeting of tumor cells

antibody targeting of tumor cells

Co-stimulation

t cell activation

Co-inhibition

Tcell inhibition

What two signals are needed for Co-stimulation

• Signal 1 - MHC to TCR

• Signal 2 - CD80 and CD86 binding to CD28 on the T cell

What two signals are needed for Co-inhibition

• Signal 1 - MHC to TCR

• Singal 2 - CD80/6 binding to CTLA-4 on tcell

what are PD1 and PDL1 interactions involved in

Homeostatic immune tolerance

what cells express PDL1

B, T, and APC

Do cancer cells have MHC 2

Yes

Do cancer cells have PDL1

Yes, which turns of T cells

Priming phase

DC activates T cell and ANTI-CTLA4 is added to block the PDL1 interaction

Effector phase

now that the PD1 has been blocked on the T cell it can attack cancer cells

Immune Checkpoint inhibators

excessivley enhance immune system via upregulation of T cells (ex. anti CTLA4)

CAR T cell therapy

Chimeric Antigen Receptor

How does CAR work

Aquire T-cells from blood → Create CAR T cell on the ARD → Grow CAR t-cells → infuse → attack cancer cells

Challenges for CAR therapy

• tumor heterogeneity and antigen escape

• CAR t-cell trafficking and infiltration

• TME might be taking too much nutrients for CAR to work