There is a growing appreciation that “immune contexture” has a significant impact on the clinical outcome for cancer patients. Thus, immunotherapies targeting immune cell migration can be developed to modulate the immune contexture in tumor microenvironment. In this slide you will learn about immune cell migration and its application in cancer immunotherapy development. As a CRO company, Creative Biolabs offers immunotherapy preclinical development services, and a full range of T cell services. Please don’t hesitate to contact us if you have any questions.

1. Immune Cell
Migration in Cancer
and Immunotherapy
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2. Contents
An Introduction to 
Immune Cell Migration
• The Immune Contexture in Cancer
• Overview of Immune Cell Migration
• Organ-specific “Area Codes” for Immune Cell Migration
• Four Classes of Leukocyte Homing Receptors
• Molecular Mechanisms of Leukocyte Extravasation
Targeting Leukocyte Migration by Immunotherapy
• Immune Cell Migration in Cancer: Current Knowledge and Open Questions
• Three Categories of Immunotherapies Targeting the Migration of Immune Cells
• Immunotherapy by Ex Vivo Modification of Immune Migration
• Immunotherapy at The Tumor Site to Enhance Immune Cell Migration
• Systemic Application of Drugs and Biologicals
Conclusions and Perspectives

3. An Introduction
to Immune Cell Migration

4. 3
The Immune Contexture in Cancer
• T and B lymphocytes, natural killer (NK) cells, macrophages, and dendritic cells (DCs) are found in
the microenvironment of solid tumors.
• Ultimately, disease outcome is determined by the complex interplay
between tumor cells, tissue cells, soluble factors within the
microenvironment, and the presence of pro‐ and anti‐tumor components
of the immune system.
• “Immune contexture” refers to the nature, location, and functionality of tumor-infiltrating leukocytes.
• Certain populations of immune cells, such as CD8+ T lymphocytes and NK cells, have the capacity to recognize
and eliminate tumor cells.
• 
Several other types of immune cells (e.g., T regulatory (Treg) cells and M2 macrophages) can exert protumor,
immunosuppressive effects within the microenvironment.

5. Overview of Immune
Cell Migration
Reference: Immunotherapy in Translational Cancer Research, First Edition. Edited by Laurence J. N.
Cooper, Elizabeth A. Mittendorf, Judy Moyes, and Sabitha Prabhakaran.
4

6. • Tissue compartments are divided by epithelial and endothelial barriers that
restrict immune cell migration.
Organ-specific “Area Codes” for
Immune Cell Migration
5
• “Lock and key” system: leukocyte homing receptors are the “keys” that allow
entry to particular tissue compartments by unlocking the endothelial barrier
when the corresponding “locks” are present.
• Distinct patterns of homing receptor expression are required for entry into each
tissue. These expression profiles are collectively described by the hypothesis of
organ-specific “area codes.”

7. Leukocyte migration to lymph node, gut, or skin, for example, requires
strikingly different patterns of homing receptor expression.
• Skin tropism is typically conferred by E- and P-selectin ligands, CCR4,
and/or CCR10.
• Gut homing requires a4b7 integrin and CCR9.
• Lymph tropism is conferred by L-selectin and CCR7.
These organ-specific area codes, combined with inflammation-induced
expression of corresponding endothelial ligands, allow fine‐tuning of
leukocyte distribution.
Organ-specific “Area Codes”
for Immune Cell Migration
6

8. Four Classes of Leukocyte Homing Receptors
Selectins (L- , P- , and E-selectin)
The selectins bind weakly to a variety of glycoprotein ligands on the surface of other cells. L-selectin is expressed
on the surface of lymphocytes. E- and P-selectin, are expressed by peripheral tissue endothelium.
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Chemokine Receptors ( A family of GPCRs)
Their chemoattractant ligands (chemokines) are secreted and displayed on the
surface of tissue cells in order to guide migration during homeostasis or in
response to inflammatory stimuli.
Selectin Ligands
Leukocytes may express ligands for E- and P -selectin that facilitate weak adhesion to peripheral endothelium. The
short-lived interactions between selectins and their ligands lead to “rolling” of leukocytes along endothelial cell
beds.
Integrins
A family of 24 heterodimers that mediates firm adhesion of leukocytes to
both endothelial cells and components of the extracellular matrix.

9. Molecular Mechanisms of Leukocyte Extravasation
• The initial tethering of leukocytes to the vascular
endothelium is mediated by low‐affinity selectin
binding.
Reference: Immunotherapy in Translational Cancer Research, First
Edition. Edited by Laurence J. N. Cooper, Elizabeth A. Mittendorf, Judy
Moyes, and Sabitha Prabhakaran.
8
• Leukocyte then rolling on the endothelial cell
surface allows for the binding of chemokine
receptors to chemokines.
• Finally, firm adhesion of leukocytes to the
endothelial bed is mediated by integrins.

10. Targeting Leukocyte Migration
by Immunotherapy

11. Immune Cell Migration in Cancer: Current
Knowledge and Open Questions
The primary objective of most immunotherapeutic strategies, such
as adoptive cell transfer and cancer vaccines, is to efficiently induce
and activate antitumor immune cells such as DCs, NK cells, and T
lymphocytes. In many cases these approaches successfully amplify
tumor immune responses in patients, yet long-lasting clinical benefit
or complete responses are reported in only a minority of cases.
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One potential explanation for this discrepancy is that, despite stimuli
that boost the immune response, immune cells
(i) do not efficiently interact with one another (for example, DCs and
CD8+ T cells) or
(ii) do not migrate to and accumulate within the tumor mass (for
example, CD8+ T cells or NK cells).

12. Three Categories of
Immunotherapies Targeting
the Migration of Immune Cells
1. Ex vivo modification of immune cells
2. Delivery of homing stimuli directly to the tumor
microenvironment
3. Systemic application of drugs and biologicals
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13. Immunotherapy
by Ex Vivo
Modification of
Immune Migration
Reference: Immunotherapy in Translational Cancer Research, First Edition. Edited by Laurence J.
N. Cooper, Elizabeth A. Mittendorf, Judy Moyes, and Sabitha Prabhakaran.
12

14. Immunotherapy at The Tumor Site to
Enhance Immune Cell Migration
Besides the direct modification of immune cells, recent research has
also focused on the delivery of immune migratory stimuli to the tumor
site - an alternative means to a similar end.
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Means to deliver chemoattractants
• Intratumoral injection
• In vivo transfection and transduction of tumor cells
• Locally applied oncolytic viruses

15. Systemic Application of Drugs and Biologicals
Anti-CTLA-4 Therapy
• CTLA-4 is located on the T cell surface and competes with the CD28
receptor to bind CD80 or CD86, thereby blocking T cell activation.
• Monoclonal antibodies against CTLA-4, such as ipilimumab, prevent
inhibitory receptor engagement and promote T cell activation (known as
“checkpoint blockade”).
• Chronic systemic treatment with anti-CTLA-4 antibodies led to increased
mobility of intratumoral T cells.
Reference: Manuel Ramos-Casals et al., Nature
Reviews Disease Primers, 2022
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16. Services from Creative Biolabs
Immuenotherapy preclinical development services
• γδ T cell therapy development
• Immune checkpoint inhibitor development
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T cell services
• T cell isolation service
• T cell activation and expansion service
• T cell characterization service
• T cell production service
• T cell cytotoxicity test
• T cell migration assay

17. Creative Biolabs
SUITE 203, 17 Ramsey Road, Shirley, NY 11967, USA
1-631-381-2994
info@creative-biolabs.com
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