4 - Tumor Immuno Flashcards
Tumor immunosurveillance hypothesis:
In normal individuals, the immune system
inhibits the growth of tumor cells
Tumor immunosurveillance: early evidence
- Immunocompetent experimental animals can reject syngeneic (i.e. of
the same genetic background) tumor cells after prior sensitization
(i.e.: tumors are immunogenic). - Tumor-specific lymphocytes can be isolated from tumor-immunized
animals. - Specific anti-tumor immunity can be passively acquired in
experimental animals by transfer of anti-tumor CD8+ T cells.
Tumor immunosurveillance: epidemiological
evidence
Immunocompromised patients
display an increased risk for
malignancies
Tumor immunosurveillance –
clinico-pathological evidence
< Immune cell infiltrates are
commonly found in solid tumors
Type, location and extent
of infiltrates may be
linked to prognosis.
Eg, higher numbers of
infiltrating T cells at the center
(CT) and invasive margin (IM)
of colorectal cancers (stages I-
III) correlate with long-term
survival. >
Innate and adaptive immunity’s tumor-killing mechanisms
tumor antigens
If syngeneic tumor cells can be rejected by the adaptive immune system, they must express antigens that can be specifically recognized: i.e. tumor antigens.
Tumor antigens can be subdivided into 2 broad categories
- tumor-specific antigens - TSAs:
restricted to tumor cells, either in a specific tumor, or in all tumors of the same type. Examples: mutated or post-transcriptionally
altered endogenous proteins, proteins encoded by oncogenic viruses, etc. Antigens due to endogenous gene mutations are also
known as “neoantigens”.
- tumor-associated antigens - TAAs:
unmutated antigens found in tumor cells, but also in normal cells, eg in restricted tissues, or at specific developmental stages
Types and examples of tumor antigens (TSAs and TAAs)
tumor-
infiltrating lymphocytes
(TILs)
Some tumor antigens can activate antigen-specific anti-tumor immune responses (potentially protective), eg: several melanoma antigens (MUM-1, tyrosinase, MAGEs), HPV E6/E7, EBV EBNA1
Can isolate antigen-specific tumor-infiltrating lymphocytes (TILs) from tumor
diagnosis, staging,
monitoring response to therapy, and screening
Other tumor antigens do not necessarily generate anti-tumor
immune responses, but are useful for diagnosis, staging,
monitoring response to therapy, and screening.
Many! You will learn them when relevant, but for example:
- Secreted/shed antigens measured in serum or urine, eg: CEA
(colorectal cancer), AFP (liver, germ cell tumors), PSA (prostate), Ig’s
(myeloma), CA125 (ovarian cancer)…
- Cell antigens detected by immunostaining of tissues or cells (histology,
flow cytometry), such as CALLA/CD10 (ALL), TdT (ALL), MPO (AML),
HER2/Neu (breast), S-100 (melanoma), synaptophysin
(neuroendocrine tumors: eg, neuroblastoma, pheochromocytoma,
etc), …
“tumor micro-
environment”
Solid tumors harbor a highly diverse set of infiltrating immune system cells, which together create a complex, functional “tumor micro-environment” (TME).
- Inflammatory “niches” may contribute to carcinogenesis and tumor progression.
- Tertiary lymphoid structures may promote immunotherapy responses
Some tumor-infiltrating immune cells inhibit tumor growth, others can promote it
Pro-tumoral
activities:
* immuno-suppression (local and/or systemic);
* angiogenesis;
* promotion of invasion and metastasis
Examples of immuno-regulatory (pro-tumoral) tumor-infiltrating cells:
- myeloid-derived suppressor cells (MDSCs),
- M2-like tumor-associated macrophages
(TAMs)
MDSCs and TAMs differentiate
and accumulate in response to
tumor-derived factors.
Physiologically, similar cell
types have been implicated in
normal tissue repair and healing
processes, and resolution of
inflammatory responses.
Signals produced in the tumor micro-environment
(including by the tumor cells themselves) directly influence the differentiation, recruitment and activity of tumor- promoting immune cell subsets
Tumor cells actively influence their micro-environment to counter the immune system’s anti-tumor mechanisms, eg:
- secretion of immunoregulatory factors (IL10, TGFb)
- recruitment/differentiation of regulatory cell subsets (T-regs, M2
MFs, TAMs, MDSCs, etc);
- active exclusion of CTLs/NKs (chemotaxis, matrix changes)
- immunosuppressive metabolic alterations, eg: arginases -> Arg
depletion; IDO-1 (indoleamine 2,3-dioxygenase) -> Trp catabolites;
hypoxia -> adenosine; ROS (immuno-toxic)
- expression of ligands for inhibitory receptors/checkpoint signals (eg,
FasL, PDL1, B7-H3);
- epitope mutation, down-regulation of target antigens, MHC and co-
stimulatory molecules
tumor immunoediting
The balance between tumor-promoting and inhibiting immunological activities contributes to tumor formation/progression vs elimination/regression.
Tumor cells evolve in response to selection by the immune system
Changes in neoplastic cell phenotypes, tumor microenvironment and infiltrating immune cells determine tumor progression in immuno-competent hosts.
Taking advantage of anti-tumor immunity for
treatment: cancer immunotherapy
Passive immunotherapy
* Therapeutic antibodies
* Adoptive cell transfer
therapy (including CAR-T)
Active immunotherapy
* Cytokines/adjuvants
* Cancer vaccines
* Oncolytic viruses
* Immune checkpoint
inhibitors
Therapeutic antibodies for cancer treatment - examples:
-
Rituximab: anti-CD20, targets B cells (CD20+) for depletion, used
for NHL. Cytotoxic (ADCC, CDC). -
Trastuzumab (Herceptin): anti-HER2, receptor antagonist, for
breast cancer. Blocks growth signals - Bevacizumab (Avastin): anti-VEGF
(colon, kidney, others). Inhibits angiogenesis. - Conjugated antibodies deliver
chemotherapy drugs or
radionuclides to tumor cells - Bi-specific T cell-engaging
(BiTE) antibodies: engineered
to have 2 different V regions to
“tether” T cells to tumor cells
Adoptive cell transfer immunotherapy (ACT)
- LAK (lymphokine-activated killer) cells: IL2-activated patient lymphocytes, trials
in the ‘80s but high toxicity -
TIL therapy: TILs are isolated from the patient’s own tumor, expanded/activated
in vitro, then reinfused (autologous transfer) - under trial (melanoma, H&N SCC,
others) -
CAR (chimeric antigen receptor) T cell therapy: genetically engineered T cells
specifically targeting tumor antigens
CAR-T cell therapy
- V regions from an Ab against a (cell surface) tumor antigen are
engineered to create an activating “chimeric antigen receptor” (CAR)
with new intracellular signaling components - Peripheral CD8+ T cells from the patient’s blood are transduced with
a viral vector encoding the CAR. - The CAR-expressing T cells are re-infused in the patient, attacking
cancer cells.
6 FDA approved: 4 to CD19 (refractory/
relapsed B cell leukemias/lymphomas: ALL,
NHL, MCL, FL), 2 to BCMA (MM).
In principle, any cell surface tumor antigen
can be a CAR-T target. In practice, it has
worked well for hematological
malignancies, but difficult for solid tumors.
CAR-NK cells and others in trial.
Immune-related adverse events (IRAEs) in CAR-T cell therapy: Cytokine release syndrome (CRS)
Extensive cytokine release by activated T cells (“on-target effects”), macrophages -> systemic inflammatory response (SIRS), “cytokine
storm”. Headache, nausea, fatigue, myalgia, joint pain, fever, tachycardia -> can progress to neurological symptoms, shock, organ failure.
Management: symptomatic -> to anti-IL6R –
(tocilizumab)
Cytokine and adjuvant therapies aim to boost anti-tumor
responses, eg:
Oncolytic viruses
recombinant viral vectors engineered to specifically target and kill cancer cells, and promote anti-tumor immune responses.
T-Vec (talimogene laherparepvec), HSV1-based (FDA 2015, melanoma)
Checkpoint receptors
Cancer cells can suppress antitumor responses by exploiting “checkpoint” mechanisms in activated T cells. Checkpoint receptors include CTLA-4 (acts on T cell-APC interactions in LNs), PD-1 (acts on T cell effector-tumor cell interaction), LAG-3
(inhibitory co-receptor) and others.
Immune checkpoint inhibitors
Immune checkpoint inhibitors: blocking antibodies to inhibitory receptors/ligands PD-1, PDL-1 and CTLA-4. Prevent signals from these molecules from turning off activated T cells.
(Anti-LAG3 approved March 2022 for melanoma)
Resistance
mechanisms to
immune checkpoint
inhibitors
ICIs have become
a staple of cancer
therapy
ICIs have become
a staple of cancer
therapy
“Off-target” AEs,
inflammatory, autoimmune,
often organ-specific.
downregulated T-regs
upregulated Th17
upregulated auto-Abs
Cancer vaccines – 1
Prophylactic vaccines: HPV, HBV
Reduction in hepatocellular carcinoma
with HepB vaccination (Qidong, China)
Reduction in cervical
cancer with HPV
vaccination (Sweden)
Cancer vaccines - 2
- Therapeutic vaccines
Sipuleucel-T for hormone therapy-resistant prostate cancer
Sipuleucel-T for hormone therapy-resistant prostate cancer. PBMCs
from the patient are isolated, APCs activated in vitro and “loaded” with a prostate-specific tumor antigen (PAP), then reinfused to prime anti-
tumor response.
-More in trial (peptides, recombinant proteins, tumor lysates, others)
Future therapeutics for cancer
Personalized cancer vaccines, tailored to each patient’s own tumor neoantigens
- Molecular sequencing of tumor genes is already carried out in the
clinical setting to assess** “tumor mutational burden “ (TMB)**
* High TMB (>10 mut/Mb), microsatellite instability correlate with positive response to immunotherapy regimens that promote anti-
tumor responses (eg, checkpoint inhibitors). - New immunogenic epitopes can be identified by sequencing.
- mRNA vaccines!
sociological considerations
Much work to be done….
- Reducing systemic effects, clinical toxicities, costs;
improving response rates
- Expanding combination therapies (multiple ICIs;
ICIs + conventional therapy; etc)
- Improving CAR-T/-NK responses in solid tumors
- Sequencing strategies
- Personalized medicine – patient/tumor-targeted
immunotherapy
