Breast cancer immune niche is a busy chatty neighbourhood with innumerable cross-talks, millions of mutual coded messages are in a dynamic flow among cancer cells and their neighbours, nonetheless among all these endless details, the most important message by far is how to evaluate, translate and thus utilise such cross talks into a substantial protocol within legitimate evidenced based background. This talk was created to wrap up this enormous field of knowledge by focusing on its harvested fruits

1. Breast Cancer immune
niche
By: Associate Professor: Dr. Lobna S. Shash
Pathology Department
Faculty of Medicine- Ain Shams University

2. Tumor microenvironment is now recognized
to represent a battery of key players rather
than passive bystanders.
Numerous cross-talks are mutually dynamic
among tumor cells and their niche.
Their language is in terms of cytokines,
chemokines, growth factors , enzymes..etc.
Such cross-talks design the fate of tumor
cells and authorize them to survive, grow,
progress and defy threats of tissue defense
or therapeutic attempts.

3. Tumorimmunemicroenvironment
(TIME)
• Provoking Observations:
1.Cancer commonly complicate inflammatory
milieu
2.Cancer prevalence  immunocompromised
individuals & experimental models.
3.Immune cells are constantly observed in
tumor stroma
4.Tumors with high immune cells company
show better prognosis
Pro-tumor?
Anti-tumor?
Pro-tumor?
Anti-tumor?

4. The battlefield between tumor
cells and TIME

6. Breast Cancer & TIME……
•WHAThappensinbreastcancer?
•Howtoidentifybreastcancers
TIMEsignatures?
•HOWtoevaluatebreastcancers
TIMEsignatures?
•WHYtoevaluatebreastcancers
TIMEsignatures?

7. Expression of immune inhibitory receptors ex. PD1, CTLA4,
LAG3 = Direct immune  effect.
Production of tumor derived immunosuppressive factors ex.
IL10, TGFβ→ Treg. , MDSCs, TAM and  cytotoxic T cells,
alter NK cells function= Indirect immune effect
Low antigenicity: Non immunogenic tumor??
WHAThappens in breast cancer?

8. Molecular- Biological identification:
By order of immunogenicity from high to low:TNBC, Her2-
neu expressing, Luminal B, LuminalA
Histologic identification:
•More common in high grade tumors
•Breast cancer with overallTIL>50%
•Breast cancers showing tertiary lymphoid structures
Immunohistochemical identification:
Good signature:  CD83 +ve dendritic cells, CD40 +ve
TAMs, CD20 +ve B lymphocytes, CD8/ CD103 +veT ILs
Poor signature: CD163 +veTAMs,  FOX3 +ve TILs??,
PDL1 +ve T Ils, PD or PDL1+ve tumor cells
•Howtoidentifybreastcancers
TIMEsignatures?

9. FANCY choices
•HOWtoevaluatebreastcancers
TIMEsignatures?

10. REAL choices
•HOWtoevaluatebreastcancers
TIMEsignatures?

11. 1) TYPE OF CELLS:
a) Routine H& E b)
IHC
(Caution: Validation of sensivity/ specificity of IHC is not
established for all subsets)
2) DISTRIBUTION OF CELLS:
a)Within stroma b) Intra-tumoral
(Caution: Avoid outside tumor border, avoid area of CNB site,
artefactual stromal crushing)
3) DENISTY OF CELLS:
(% of stroma): NOT hotspots, just overall % +/- presence of TLS
(Caution: at least one whole section in x200 magnification
power, full tumor sections better than CNB material, NO
THRESHOLD yet validated as clinically significant by evidence
based studies however 50-60% of stroma is suggested)=
Lymphocyte predominant breast carcinoma (LPBC)

12. Predictive/ prognostic value for response to therapy :
-Hormone negative tumors with >50% TILs are likely to
develop CPR with neoadjuvant chemotherapy and better DFS
and OS.
-  TAM, TAN/TIL ratio are reported to carry poor prognostic
value in both hormone positive and hormone negative
cancers.
-  B lymphocytes, plasma cells is a good prognostic
indicator in TNBC
Immergence of immune targeted therapy:
1. Breast cancer vaccines 2. Monoclonal antibodies (MAbs)
3. Antibody-drug conjugates (ADCs)
4. Checkpoint inhibitors
5. Stimulatory molecule agonist antibodies;
6. Combination immunotherapy trials;
7. Enhance the immune-mediated effect of chemotherapy.
•WHYtoevaluateTIMEsignatures?
BASIC PRINCIPAL
Initiate or create a self-sustaining cycle of cancer immunity enabling it to
amplify and propagate an anticancer response
OPTIMUM TARGET
Approaches involving selective targeting of the rate-limiting step or steps in
any given patient.

13. Take home message:
• Tumor cells and their microenviroment are
intimate partners in the carcinogenesis
process from birth to death.
• Like other components of tumor
microenvironment TIME is a double ended
sword that exerts pro and anti- tumor effects.
• Understanding breast cancer immunogenicity
in general and the peculiar features of each
breast cancer case is mandatory for predictive
and prognostic foretelling of its outcome.

14. •Immunotherapy is a new fruit of the ever
growing personalized medicine field with
promising benefits.
•To enable harvesting this fruit many challenges
still need to be overcome to transfer the
success of experimental models to clinical trials
and thus clinical practice.
•Awareness of our particular limitations and
tailoring our practice accordingly is currently
inevitable and requires creative solutions and
close clinicopathological interaction to create
our own protocol of practice catching up with
these growing advents.

15. THANK YOU