TNFR2 is a legitimate new ICP target of the anti-cancer arsenal

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Patient eligibility for alloHSCT

Considering one given patient, its eligibility for alloHSCT will depend on a broad range of parameters regarding the patient himself or its malignancy type. The availability of a suitable donor will also be clearly determining. Historically, bone-marrow transplant was mainly indicated for patient with severe blood cancer, refractory to the usual therapies and in a fit physical condition. Until now, no global consensus exists even if major improvements for conditioning regimens had permitted to enlarge graft candidate profiles. The decision to graft is often taken on a case-by-case basis after a collegial decision of the transplant centre physicians. A pre-transplant study of the above-mentioned variables establishes a benefit-risk assessment which is carefully explained and discussed with the patient.

Underlying disease impact

In its last report from 2018, the French Biomedical Agency (Agence de la biomédecine (ABM)) counted 1946 alloHSCT performed in France for a total of 1 905 recipients, all HSC sources and donor type included. Among these patients, 87,8% were suffering from haematological malignancies. The largest indication of alloHSCT in 2018 remains for patients with acute myeloblastic leukaemia (AML, 39,3%), followed by those with acute lymphoblastic leukaemia (ALL, 13,9%), myelodysplastic syndromes (MDS, 11,8%) and non-Hodgkin lymphomas (NHL, 7,7%) as illustrated in Figure 1. Overall, this range of indications is identical whether the donor is related to the patient or not.
Regardless of the malignancy, the risks of mortality and morbidity associated with alloHSCT are always compared with those of non-transplant therapeutic options. Generally, since this cell therapy is at high risk of heavy short- and long-term complications, it is suggested for chemo-sensitive patients with a poorer prognosis. Concerning both types of acute leukaemia, alloHSCT is used as a post-remission therapy, after the first or a subsequent remission (Deeg and Sandmaier, 2019). For other neoplasms for which specific therapeutic tools exist, alloHSCT constitutes an alternative for tumours that are not sensitive to the standard treatment. For example, for patients with chronic myeloid leukaemia that are resistant or intolerant to tyrosine kinase inhibitors.
Besides, the type of underlying malignancy and previous treatments impact the disease stage and cytogenetic status at the time of alloHSCT. Both of these factors are the strongest known post-graft relapse determinants. For this reason, the choice of alloHSCT timing is crucial for the clinicians to control, as far as possible, at which stage of the disease the transplantation is carried out. To help this decision, several studies allowed to create alloHSCT risk scales based on cytogenetic factors and disease aggressiveness. The Center for International Blood and Marrow Transplant Research (CIBMTR) combined data from 13 131 allografted patients between 2008 and 2010 to create a refined version of their previous disease risk index (Armand et al., 2014). This index stratifies for each disease type the risk of a specific population of patients grouped by karyotype anomalies and cancer status (in remission or relapsing). Considering a specific pathology, the index gives the estimated overall survival (OS) at two years for risk groups identified as « low », « intermediate », « high », and « very high ». An example for acute leukaemia is shown in Figure 2. Unexpectedly for ALL, Philadelphia chromosome was not modifying post-graft patient survival and is consequently not taken in account. Inversely, adverse cytogenetics considerably decrease the estimated two-year OS from 66 (low risk) to 33% (high risk) for AML patients in complete remission (CR).

Individual factors impact

It is generally acknowledged that older age, significant comorbidities, relapsing or unresponsive malignancy, and prior aggressive therapies are factors associated with an increased risk of morbidity and mortality after alloHSCT. Physicians are currently unable to robustly predict who is more likely to develop post-graft complications. Pretransplant patient’s characteristics are determining for the graft protocol choice and both influence post-transplant events such as the risk and severity of GvHD and infections. In this regard, individual factors are carefully reviewed for each patient, but none of these factors is nowadays an absolute graft contraindication.
The median alloHSCT patient age has been in constant augmentation over the last centuries, changing drastically from 25 in the 1980s, to 39 in the 1990s, reaching 46 in the 2000s (CIBMTR database). France is following the global tendency with an increasing average age of alloHSCT patients (ABM 2018 report). Between 2012 and 2018 an increase of 5 years was observed, changing from 41 to 46 years old. When excluding paediatric patients (< 18 years old) as displayed in Figure 3, the average age of adult patients changes from 48 to 53 in this period. Notably, for the year of the report, 53% of the allografted adults had more than 55 years old, when this frequency was 40,1% in 2012. This impressive enlargement of the indication to older patients is due to the recent progress in low toxicity conditioning regimen (nonmyeloablative (NMA) and reduced intensity (RIC) ones).

GvT effect: Definition and clinical evidences

Two main elements in alloHSCT account for protection from relapse: the pre-graft preparative regimen and the presence of donor T cells naturally contained inside the graft. Conditioning primarily mediates relapse protection in the early phase after transplantation, from 0 to 12 months, while the effect of donor T cells through the GvT effect occurs usually after the first year (Biernacki et al., 2020). As previously mentioned (Chapter I.B.5. Figure 6), depending on the conditioning intensity the requirement in terms of GvT strength differs. It is of particular importance for low-intensity options NMA and RIC regimens, whereas conditioning and GvT effect both contribute to relapse protection when using intensive myeloablative regimens (Inamoto et al., 2011; Scott et al., 2017).
GvT has been first recognized in the pioneer allograft experiment sets performed by Barnes et al., they reported that leukemic mice treated with a subtherapeutic dose of radiation and a syngeneic (identical twin) graft transplant were more likely to relapse than mice given an allogeneic stem cell transplant (Barnes et al., 1956). They hypothesized that the allogeneic graft contained cells with immune reactivity necessary for eradicating residual leukaemia cells.
They also noted that recipients of allogeneic grafts, though less likely to relapse, died of a “wasting syndrome” now recognized as GvHD. Thus, in addition to describing GvT, these experiments highlighted for the first time the intricate relationship between GvT and GvHD. Later on, the importance of donor T cells in mediating GvT was originally inferred from clinical data demonstrating increased relapse risk with extensive ex vivo T cell depletion from donor grafts before infusion into patients (Horowitz et al., 1990; Marmont et al., 1991). Another important aspect in this demonstration has been the observation of a higher relapse rate in syngeneic graft recipient compared to matched-HLA allogeneic ones, indicating that even in well-matched individuals, subtle degrees of mismatch can induce the beneficial effect of GVT (Weiden et al., 1979). The discovery of the polymorphic genes that encode minor histocompatibility antigens permitted to explain the observations about HLA-identical-sibling.
T-cell responses to minor histocompatibility antigens are responsible for the antileukemic activity, but also cause GvHD (Bleakley and Riddell, 2004). NK cells do have a role to play in GvT effect and GvHD in HLA-mismatched grafts, but their action is out of scope of this thesis (Hu and Liu, 2017).

Establishment of the alloreactive response

Conditioning regimen is not only responsible for the early antitumour action by directly depleting healthy as well as malignant hematopoietic cells, but also is crucial to initiate the long-term GvT effect. In consequence, the delayed transfer of alloreactive T cells in chimaera mice does not induce GvHD and results in reduced GvT effect (Chakraverty, 2006, 2008; Li et al., 2015). Indeed, chemotherapeutic agents and radiations used in alloHSCT preparative regimens aim to be mainly toxic for the hematopoietic compartment while sparing the damages on other tissues, but they still generate DNA strand breaks and reactive oxygen species in the host tissues (Kim et al., 2014; Mauch et al., 1995). In fine, it induces epithelium and mesenchymal cell death by necrosis or apoptosis (Sonis et al., 2004; Blijlevens and Sonis, 2007). These tissue damages will generate danger signals emanating from both the host (damage-associated molecular patterns (DAMP)) and its commensal flora (pathogenassociated molecular patterns (PAMP)), contributing to the activation of local antigenpresenting cell (APC) that will, in turn, activate alloreactive T cells (Brubaker et al., 2015; Jones et al., 1971). DAMP include a myriad of pro-inflammatory cytokines, such as TNF-, and chemokines, which together can increase the expression of adhesion molecules, HLA antigens and costimulatory molecules on host APC (Ferrara et al., 2009). An important aspect of this process is the implication, not only of the donor APC derived from HSC but also those from the host, able to present host HLA and minor antigens to alloreactive donor T cells. This coexistence is transitory since recipient APC will be progressively killed by donor T cells and replaced by bone marrow emerging donor APC, able to present recipient antigens using crosspresentation (Shlomchik, 2007; Wang et al., 2011). Therefore, donor APC are not required for GvHD initiation, but they cause its maintenance and are mandatory for a long-term GvT effect (Matte et al., 2004; Reddy et al., 2005). Many studies have attempted to identify the critical APC subsets involved, predicated on the notion that deletion may prevent GVHD, however it appears that if one subset is sufficient to induce GvHD, none is necessary (Koyama and Hill, 2016).

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Effector/memory profile

After alloHSCT, donor T cells display diverse phenotypes that correlate with their function.  Alloreactive T cells co-exist with non-host-reactive donor T cells which are beneficial for peripheral T-cell reconstitution, and both subsets diverge in phenotype and division rate (Maury et al., 2001). Additionally, alloreactive T cells phenotype appear to be different depending on their capacity to induce GvHD or GvT. Indeed, GvHD induction can be limited by   depletion of the naïve T cell population from the graft in mice, a strategy that seems to be confirmed in patients, without impairing GvT effect (Bleakley et al., 2014, 2015). In contrast, T cells responsible for the antitumour effect appear to come from the CD4+ and CD8+ central memory and the effector memory populations (Dutt et al., 2011; Zhang et al., 2004; Zheng et al., 2008, 2009, 2014). Furthermore, central memory T cells show a higher migration potential than effector memory cells in the secondary lymphoid organs resulting in a better antitumour efficacy (Klebanoff et al., 2005).

T helper subsets

In the same vein, the profile of donor T cells differentiation in Th1/2/17 has been deeply explored trying to detect a difference between GvHD and GvL main actors. Historically, GvHD have been thought to be driven only by Th1 differentiation profile, among others because of  the very high expression of TNF- and IFN-γ in target organs (Antin and Ferrara, 1992; Hill et al., 1997). At the contrary, Th2 cells were for long considered as a protective population, and the blocking of Th2 differentiation has been strongly associated with GvHD amplification (Fowler et al., 1994, Tawara et al., 2008). However, the reality is less straightforward since both Th1 and Th2 are required for the appearance of lesions in the gut for instance, suggesting that both populations potentially have different functions depending on the tissue considered (Nikolic et al., 2000). Regarding Th profiles involved in the antitumour action post-allograft, less data is available for now. Th1 cells are also the principal mediator of the GvT effect, and Th2 CD4+ do not seem necessary for its application, while cytotoxic CD8+ type 2 could have a role (Yang et al., 2002). Lastly, deficiency in Th17 cells induce a diminution of Th1 cells to the benefit of Treg cells, resulting in a milder GvHD, due in part to the reduced migration of T cells toward the gut (Hanash et al., 2011). Notably, this subset does not appear to have a role in the tumour eradication.

Table of contents :

Avant-propos
Allogeneic hematopoietic stem-cells transplantation
A. Discovery and principle
B. Clinical settings
1. Overview
2. Patient eligibility for alloHSCT
a) Underlying disease impact
b) Individual factors impact
3. Sources of hematopoietic stem cells
4. Donor selection
5. Preparative regimens
6. Post-alloHSCT monitoring
a) Engraftment and chimerism
b) Short- and long-term care
7. Complications and management
a) Relapses and post-alloHSCT secondary malignancies
b) Infectious risk
c) Graft-versus-host disease
(1) Acute
(2) Chronic
(3) Preventive action against GvHD
(a) aGvHD risk factors
(b) Current immunosuppressive prophylaxis
(c) Partial T cell depletion strategies
Immunotherapeutic effect of alloHSCT
A. GvT effect: Definition and clinical evidences
B. Establishment of the alloreactive response
C. Allogeneic effector phase
1. T cells trafficking
2. Effector/memory profile
3. T helper subsets
4. Antigen specificity
5. Cytotoxic mechanisms of tumour cell elimination
D. Causes of relapse
a) Tumour cells intrinsic mechanisms of evasion
b) Microenvironment-induced evasion
E. Clinical strategies for a better GvT effect
1. Toward a relapse prediction
2. Adoptive cell therapies
a) DLI
b) Chimeric antigen receptor T cells
3. Anti-immune checkpoints
The role of regulatory T cells in cancer
A. Fresh perspectives in oncology
B. Treg biology
1. Discovery and key features
2. Treg ontogeny and lineage plasticity
3. Phenotypic characterization
4. Mechanisms of suppression
a) Described suppressing mechanisms
b) Dynamic aspects of Treg suppressive function
5. CD8+ Treg resurgence
C. Treg dysregulation in cancer
1. Treg association with cancer progression
a) State of the art in solid and blood cancers
b) Unravelling the literature divergences
2. Treg interactions with the TME
a) Tumour infiltration and activation
b) Suppression of the anti-tumoral effector response
3. Effect of the current immunotherapies on Treg
D. Interfering with Treg immune suppression
1. Rational behind Treg blockade
2. Indirect anti-Treg strategies
a) Chemotherapeutic agents
b) Induction of “suppression-proof” Teff
3. Treg-specific blockade
a) Freezing Treg migration
b) Bypassing Treg differentiation
c) IL-2/CD25-focused strategies
d) Turning off Treg activation signals
e) Converting Treg into pro-inflammatory cells
The TNF-α/TNFR2 pathway: a new ICP to target
A. Historical point of view
B. Comprehensive overview of TNF- signalling
1. Actors involved and their expression pattern
2. Signalling pathways
C. TNFR2 critical function in tolerance
1. For immune homeostasis maintenance
2. Under inflammatory conditions
D. TNF- implication in alloHSCT
E. TNF-α/TNFR2 role in malignancies
1. In the TME
2. For cancer cells
F. Specific TNFR2 pathway blockade in cancer
1. Rationale
2. Pioneer approaches
TNFR2 inhibition blocks tumour growth post-alloHSCT
A. Mouse model of post-alloHSCT relapse: advantages and limitations
B. On the role of TNFR2 expression on tumour cells
C. On the risk of GvHD induction after anti-TNFR2 treatment
TNFR2 blockade spurs the alloimmune response
A. By helping effector response initiation
B. By inducing Treg stability and function decline
C. Integrative view of TNFR2 inhibition impact in alloHSCT
TNFR2 is a legitimate new ICP target of the anti-cancer arsenal
A. TNF- pathway as a promising anti-cancer agent once more
B. TNFR2 attractive pattern of expression
C. TNFR2 modulation of Teff/Treg equilibrium
D. Potential side effects for TNFR2 blockade
E. Activation versus TNFR2 blockade in tumoral context
F. Hopes for combined therapies
TRANSLATIONAL PERSPECTIVES
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